Heteroaryl-ketone fused azadecalin glucocorticoid receptor modulators

ABSTRACT

The present invention provides heteroaryl ketone fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/570,839, filed Sep. 13, 2019, which is a continuation of U.S.application Ser. No. 15/889,494, filed Feb. 6, 2018 (now U.S. Pat. No.10,456,392, issued Oct. 29, 2019), which is a continuation of U.S.application Ser. No. 15/621,013, filed Jun. 13, 2017 (now U.S. Pat. No.9,956,216, issued May 1, 2018), which is a continuation of U.S.application Ser. No. 15/013,218, filed Feb. 2, 2016 (now U.S. Pat. No.9,707,223, issued Jul. 18, 2017), which is a divisional of U.S.application Ser. No. 14/487,347, filed Sep. 16, 2014 (now U.S. Pat. No.9,273,047, issued Mar. 1, 2016), which is a divisional of U.S.application Ser. No. 13/901,946, filed May 24, 2013 (now U.S. Pat. No.8,859,774, issued Oct. 14, 2014), which claims priority to U.S.Provisional Application Nos. 61/781,269, filed Mar. 14, 2013,61/759,520, filed Feb. 1, 2013, 61/715,907, filed Oct. 19, 2012,61/691,083, filed Aug. 20, 2012, and 61/651,669, filed May 25, 2012, allof the disclosures of which are incorporated in their entireties hereinfor all purposes.

BACKGROUND OF THE INVENTION

In most species, including man, the physiological glucocorticoid iscortisol (hydrocortisone). Glucocorticoids are secreted in response toACTH (corticotropin), which shows both circadian rhythm variation andelevations in response to stress and food. Cortisol levels areresponsive within minutes to many physical and psychological stresses,including trauma, surgery, exercise, anxiety and depression. Cortisol isa steroid and acts by binding to an intracellular, glucocorticoidreceptor (GR). In man, glucocorticoid receptors are present in twoforms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-betaisoform which lacks the 50 carboxy terminal residues. Since theseinclude the ligand binding domain, GR-beta is unable to bind ligand, isconstitutively localized in the nucleus, and is transcriptionallyinactive. The GR is also known as the GR-II receptor.

The biologic effects of cortisol, including those caused byhypercortisolemia, can be modulated at the GR level using receptormodulators, such as agonists, partial agonists and antagonists. Severaldifferent classes of agents are able to block the physiologic effects ofGR-agonist binding. These antagonists include compositions which, bybinding to GR, block the ability of an agonist to effectively bind toand/or activate the GR. One such known GR antagonist, mifepristone, hasbeen found to be an effective anti-glucocorticoid agent in humans(Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone bindsto the GR with high affinity, with a dissociation constant (K_(d)) of10⁻⁹M (Cadepond (1997) Annu. Rev. Med. 48:129). What is needed in theart are new compositions and methods for modulating GR receptors.Surprisingly, the present invention meets these and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention provides many fused azadecalin compounds. In someembodiments, the present invention provides compounds having thestructure of formula I:

wherein R¹ of formula I is a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 4 heteroatoms which can each independently be N, Oor S, optionally substituted with 1-4 groups which can eachindependently be R^(1a). Each R^(1a) of formula I can independently behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl.Ring J of formula I can be a cycloalkyl ring, a heterocycloalkyl ring,an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl andheteroaryl rings have from 5 to 6 ring members and from 1 to 4heteroatoms which can each independently be N, O or S. Each R² offormula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b),—SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2c) groups. Alternatively, two R² groups linkedto the same carbon can be combined to form an oxo group (═O).Alternatively, two R² groups can be combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms whereineach can independently be N, O or S, wherein the heterocycloalkyl ringis optionally substituted with from 1 to 3 R^(2d) groups. R^(2a) andR^(2b) of formula I can each independently be hydrogen or C₁₋₆ alkyl.Each R^(2c) can independently be hydrogen, halogen, hydroxy, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —CN, or —NR^(2a)R^(2b). Each R^(2d) canindependently be hydrogen or C₁₋₆ alkyl, or two R^(2d) groups attachedto the same ring atom can be combined to form (═O). R³ of formula I canbe phenyl or pyridyl, each optionally substituted with 1-4 R^(3a)groups. Each R^(3a) of formula I can independently be hydrogen, halogen,or C₁₋₆ haloalkyl. Subscript n of formula I can be an integer from 0 to3. The compounds of formula I can also be the salts and isomers thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition including a pharmaceutically acceptable excipient and thecompound of formula I.

In some embodiments, the present invention provides a method ofmodulating a glucocorticoid receptor, the method including contacting aglucocorticoid receptor with a compound of formula I, thereby modulatingthe glucocorticoid receptor.

In some embodiments, the present invention provides a method of treatinga disorder through modulating a glucocorticoid receptor, the methodincluding administering to a subject in need of such treatment, atherapeutically effective amount of a compound of formula I, therebytreating the disorder.

In some embodiments, the present invention provides a method of treatinga disorder through antagonizing a glucocorticoid receptor, the methodincluding administering to a subject in need of such treatment, aneffective amount of the compound of formula I, thereby treating thedisorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 show various synthetic schemes for making the compounds ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION I. General

The present invention provides compounds capable of modulating aglucocorticoid receptor (GR) and thereby providing beneficialtherapeutic effects. The compounds include heteroaryl ketone fusedazadecalins. The present invention also provides methods of treatingdiseases and disorders by modulating a GR receptor with the compounds ofthe present invention.

II. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groupshaving up to 20 carbons atoms, such as, but not limited to heptyl,octyl, nonyl, decyl, etc.

“Alkylene” refers to a straight or branched, saturated, aliphaticradical having the number of carbon atoms indicated, and linking atleast two other groups, i.e., a divalent hydrocarbon radical. The twomoieties linked to the alkylene can be linked to the same atom ordifferent atoms of the alkylene group. For instance, a straight chainalkylene can be the bivalent radical of —(CH₂)_(n)—, where n is 1, 2, 3,4, 5 or 6. Representative alkylene groups include, but are not limitedto, methylene, ethylene, propylene, isopropylene, butylene, isobutylene,sec-butylene, pentylene and hexylene.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Alkyl-Alkoxy” refers to a radical having an alkyl component and analkoxy component, where the alkyl component links the alkoxy componentto the point of attachment. The alkyl component is as defined above,except that the alkyl component is at least divalent, an alkylene, tolink to the alkoxy component and to the point of attachment. The alkylcomponent can include any number of carbons, such as C₀₋₆, C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₁₋₆, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆and C₅₋₆. In some instances, the alkyl component can be absent. Thealkoxy component is as defined above.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆. For example, haloalkyl includes trifluoromethyl, fluoromethyl,etc. In some instances, the term “perfluoro” can be used to define acompound or radical where all the hydrogens are replaced with fluorine.For example, perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₄₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Alkyl-cycloalkyl” refers to a radical having an alkyl component and acycloalkyl component, where the alkyl component links the cycloalkylcomponent to the point of attachment. The alkyl component is as definedabove, except that the alkyl component is at least divalent, analkylene, to link to the cycloalkyl component and to the point ofattachment. In some instances, the alkyl component can be absent. Thealkyl component can include any number of carbons, such as C₁₋₆, C₁₋₂,C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆and C₅₋₆. The cycloalkyl component is as defined within. Exemplaryalkyl-cycloalkyl groups include, but are not limited to,methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl andmethyl-cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O and S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8,6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, having a methylene linking group. Some arylgroups have from 6 to 12 ring members, such as phenyl, naphthyl orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Arylene” refers to an aryl group, as defined above, linking at leasttwo other groups. The two moieties linked to the aryl are linked todifferent atoms of the aryl. Arylene groups can be substituted orunsubstituted.

“Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O or S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heteroaryl groups can include any number of ringatoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8,3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable numberof heteroatoms can be included in the heteroaryl groups, such as 1, 2,3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members andfrom 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, orfrom 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroarylgroup can include groups such as pyrrole, pyridine, imidazole, pyrazole,triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-,1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole,oxazole, and isoxazole. The heteroaryl groups can also be fused toaromatic ring systems, such as a phenyl ring, to form members including,but not limited to, benzopyrroles such as indole and isoindole,benzopyridines such as quinoline and isoquinoline, benzopyrazine(quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such asphthalazine and cinnoline, benzothiophene, and benzofuran. Otherheteroaryl groups include heteroaryl rings linked by a bond, such asbipyridine. Heteroaryl groups can be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline,benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroarylene” refers to a heteroaryl group, as defined above, linkingat least two other groups. The two moieties linked to the heteroaryl arelinked to different atoms of the heteroaryl. Heteroarylene groups can besubstituted or unsubstituted.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples of pharmaceuticallyacceptable salts are mineral acid (hydrochloric acid, hydrobromic acid,phosphoric acid, and the like) salts, organic acid (acetic acid,propionic acid, glutamic acid, citric acid and the like) salts,quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.It is understood that the pharmaceutically acceptable salts arenon-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

“Hydrate” refers to a compound that is complexed to at least one watermolecule. The compounds of the present invention can be complexed withfrom 1 to 10 water molecules.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of skill in the art will recognizethat other pharmaceutical excipients are useful in the presentinvention.

“Modulating a glucocorticoid receptor” refers to methods for adjustingthe response of a glucocorticoid receptor towards glucocorticoids,glucocorticoid antagonists, agonists, and partial agonists. The methodsinclude contacting a glucocorticoid receptor with an effective amount ofeither an antagonist, an agonist, or a partial agonist and detecting achange in GR activity.

“Glucocorticoid receptor” (“GR”) refers to a family of intracellularreceptors which specifically bind to cortisol and/or cortisol analogs(e.g. dexamethasone). The glucocorticoid receptor is also referred to asthe cortisol receptor. The term includes isoforms of GR, recombinant GRand mutated GR.

“Glucocorticoid receptor antagonist” refers to any composition orcompound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “specificglucocorticoid receptor antagonist” refers to any composition orcompound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” we intend the drug topreferentially bind to the GR rather than other nuclear receptors, suchas mineralocorticoid receptor (MR) or progesterone receptor (PR).

“GR modulator” refers to compounds that agonize and/or antagonize theglucocorticoid receptor and are defined as compounds of Formula I below.

“Anti-inflammatory glucocorticosteroid” refers to a class of steroidhormones that bind to the glucocorticoid receptor and reduceinflammation. Examples of anti-inflammatory glucocorticosteroidsinclude, but are not limited to, cortisol (the physiologicalglucocorticoid) as well as alclometasone, betamethasone, budesonide,ciclesonide, clobetasol, clocortolone, deprodone, desonide,dexamethasone, difluprednate, flunisolide, fluocinolone, fluticasone,halcinonide, halometasone, halopredone, hydrocortisone, loteprednol,methylprednisolone, mometasone, naflocort, oxazacort, paramethasone,prednicarbate, prednisolone, prednisone, triamcinolone, trimexolone, andulobetasol. Glucocorticosteroids are part of a class of compounds calledcorticosteroids that also includes mineralocorticosteroids. Theanti-inflammatory glucocorticosteroids of the present invention bind toglucocorticoid receptor and not to the mineralocorticoid receptor, alsoknown as the glucocorticoid receptor I (GRI).

“GR induced transactivation” refers to gene expression induced bybinding of a GR agonist to a glucocorticoid receptor. For example, GRinduced transactivation can occur when an anti-inflammatoryglucocorticosteroid, such as dexamethasone, binds to a glucocorticoidreceptor. In the present invention, inhibition of GR inducedtransactivation occurs with at least 25% inhibition of the GR inducedtransactivation activity.

“GR induced transrepression” refers to inhibition of gene expressioninduced by binding of a GR agonist to a glucocorticoid receptor. The GRmodulators of the present invention can have minimal effect on GRinduced transrepression. In the present invention, substantially notinhibiting GR-induced transrepression is when GR-induced transrepressionactivity in the presence of the GR modulator is at least 50% of theactivity observed in the absence of the GR modulator.

“Contacting” refers to the process of bringing into contact at least twodistinct species such that they can react with one another or interactsuch that one has an effect on the other.

“Treat”, “treating” and “treatment” refer to any indicia of success inthe treatment or amelioration of an injury, pathology or condition,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the injury, pathology orcondition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; improving a patient's physical or mental well-being. Thetreatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals and othernon-mammalian animals.

“Disorder” or “condition” refer to a state of being or health status ofa patient or subject capable of being treated with the glucocorticoidreceptor modulators of the present invention. Examples of disorders orconditions include, but are not limited to, obesity, hypertension,depression, anxiety, and Cushing's Syndrome.

“Antagonizing” refers to blocking the binding of an agonist at areceptor molecule or to inhibiting the signal produced by areceptor-agonist. A receptor antagonist blocks or dampensagonist-mediated responses.

“Therapeutically effective amount” refers to an amount of a conjugatedfunctional agent or of a pharmaceutical composition useful for treatingor ameliorating an identified disease or condition, or for exhibiting adetectable therapeutic or inhibitory effect. The effect can be detectedby any assay method known in the art.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, or physiological conditions.

III. Compounds

The present invention provides many fused azadecalin compounds. In someembodiments, the present invention provides compounds having thestructure of formula I:

wherein R¹ of formula I is a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 4 heteroatoms which can each independently be N, Oor S, optionally substituted with 1-4 groups which can eachindependently be R^(1a). Each R^(1a) of formula I can independently behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl.Ring J of formula I can be a cycloalkyl ring, a heterocycloalkyl ring,an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl andheteroaryl rings have from 5 to 6 ring members and from 1 to 4heteroatoms which can each independently be N, O or S. Each R² offormula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b),—SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2′) groups. Alternatively, two R² groups linkedto the same carbon can be combined to form an oxo group (═O).Alternatively, two R² groups can be combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms whereineach can independently be N, O or S, wherein the heterocycloalkyl ringis optionally substituted with from 1 to 3 R^(2d) groups. R^(2a) andR^(2b) of formula I can each independently be hydrogen or C₁₋₆ alkyl.Each R^(2′) can independently be hydrogen, halogen, hydroxy, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —CN, or —NR^(2a)R^(2b). Each R^(2d) canindependently be hydrogen or C₁₋₆ alkyl, or two R^(2d) groups attachedto the same ring atom can be combined to form (═O). R³ of formula I canbe phenyl or pyridyl, each optionally substituted with 1-4 R^(1a)groups. Each R^(1a) of formula I can independently be hydrogen, halogen,or C₁₋₆ haloalkyl. Subscript n of formula I can be an integer from 0 to3. The compounds of formula I can also be the salts and isomers thereof.

In some embodiments, wherein R¹ of formula I can be a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms which caneach independently be N, O or S, optionally substituted with 1-4 groupswhich can each independently be R^(1a). Each R^(1a) of formula I canindependently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —CN, C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl.Ring J of formula I can be a cycloalkyl ring, a heterocycloalkyl ring,an aryl ring or a heteroaryl ring, wherein the heterocycloalkyl andheteroaryl rings have from 5 to 6 ring members and from 1 to 3heteroatoms which can each independently be N, O or S. Each R² offormula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN, —NR^(2a)R^(2b), C₃₋₈cycloalkyl, or C₃₋₈ heterocycloalkyl, wherein the heterocycloalkylgroups are optionally substituted with 1-4 R^(2c) groups. R^(2a) andR^(2b) of formula I can each independently be hydrogen or C₁₋₆ alkyl.Each R^(2c) can independently be hydrogen, halogen, hydroxy, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —CN, or —NR^(2a)R^(2b). R³ of formula I can bephenyl or pyridyl, each optionally substituted with 1-4 R^(1a) groups.Each R^(1a) of formula I can independently be hydrogen, halogen, or C₁₋₆haloalkyl. Subscript n of formula I can be an integer from 0 to 3. Thecompounds of formula I can also be the salts and isomers thereof.

In some embodiments, R¹ can be a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 3 heteroatoms which each can independently be N, Oor S, optionally substituted with 1-4 groups which can eachindependently be R^(1a). Each R^(1a) can independently be hydrogen orC₁₋₆ alkyl. Ring J can be tetrahydrofuran, phenyl or pyridyl. Each R²can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —CN, —NR^(2a)R^(2b), C₃₋₈ cycloalkyl, or C₃₋₈heterocycloalkyl. R^(2a) and R^(2b) can each independently be hydrogenor C₁₋₆ alkyl. R³ can be phenyl or pyridyl. R^(3a) can be F. Subscript ncan be 0 or 1. In some embodiments, each R^(1a) can independently behydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₁₋₆ alkoxy.

In some embodiments, R¹ can be a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 3 heteroatoms which can each independently be N, Oor S, optionally substituted with 1-4 groups which can eachindependently be R^(1a). Each R^(1a) can independently be hydrogen orC₁₋₆ alkyl. Ring J can be phenyl or pyridyl. Each R² can independentlybe hydrogen, halogen, C₁₋₆ haloalkyl, —CN or C₅₋₆ heterocycloalkyl. R³can be phenyl or pyridyl. R^(3a) can be F. In some embodiments, eachR^(1a) can independently be hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, orC₁₋₆ alkoxy.

The compounds of the present invention include at least one stereogeniccenter at the bridgehead carbon. Accordingly, the compounds can includea mixture of isomers, including enantiomers in a racemic mixture, or inenantiomerically pure mixtures that are substantially the R- orS-isomer. In some embodiments, the compounds of formula I can have thefollowing structure:

Any suitable heteroaryl can be used for R¹ in the compounds of thepresent invention, as defined in the definitions above. In someembodiments, the heteroaryl of R¹ can have from 5 to 6 ring members andfrom 1 to 4 heteroatoms which can each independently be N, O or S,optionally substituted with 1-4 groups which can each independently beR^(1a). In some embodiments, the heteroaryl of R¹ can be pyrrole,pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole,oxadiazole, thiophene, thiazole, isothiazole, thiadiazole, pyridine,pyrazine, pyrimidine, or pyridazine. In some embodiments, the heteroarylof R¹ can be 2-pyrrole, 3-pyrrole, 1-pyrazole, 3-pyrazole, 4-pyrazole,5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl,1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-furan,2-oxazole, 4-oxazole, 5-oxazole, 3-isoxazole, 4-isooxazole,5-isooxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene,2-thiazole, 4-thiazole, 5-thiazole, 3-isothiazole, 4-isothiazole,5-isothiazole, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl,1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine,2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine,4-pyridazine, 5-pyridazine, or 6-pyridazine. In some embodiments, theheteroaryl of R¹ can be pyrazole, imidazole, triazole, furan, oxazole,oxadiazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine. Insome embodiments, the heteroaryl of R¹ can be imidazole, furan, oxazole,oxadiazole, thiophene, thiazole, or pyridine. In some embodiments, theheteroaryl of R¹ can be 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole,2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl,1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 2-furan,3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine,4-pyrimidine, 5-pyrimidine, or 6-pyrimidine. In some embodiments, theheteroaryl of R¹ can be 3-pyrazole, 4-pyrazole, 2-imidazole,1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl,2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine,4-pyridine, pyrazine, or 2-pyrimidine. In some embodiments, theheteroaryl of R¹ can be 2-imidazole, 4-imidazole, 5-imidazole, 2-furan,3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, or 4-pyridine.

In some embodiments, the heteroaryl of R¹ can be optionally substitutedwith 1-4 groups which can each independently be R^(1a). In someembodiments, each R^(1a) can independently be hydrogen, C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN, N-oxide,C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl. In some embodiments, eachR^(1a) can independently be hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy or C₃₋₈ heterocycloalkyl. In some embodiments, each R^(1a) canindependently be hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₁₋₆ alkoxy.In some embodiments, each R^(1a) can independently be hydrogen, C₁₋₆alkyl, or C₁₋₆ haloalkyl. In some embodiments, each R^(1a) canindependently be hydrogen or C₁₋₆ alkyl. The alkyl of R^(1a) can be anysuitable alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, andhexyl, among others. In some embodiments, each R^(1a) can independentlybe hydrogen, methyl, ethyl, trifluoromethyl, methoxy, or pyrrolidinyl.In some embodiments, each R^(1a) can independently be hydrogen, methyl,ethyl, trifluoromethyl, or methoxy. In some embodiments, each R^(1a) canindependently be hydrogen or methyl.

Ring J of formula I can be any suitable ring. In some embodiments, ringJ of formula I can be a cycloalkyl ring, a heterocycloalkyl ring, anaryl ring or a heteroaryl ring, wherein the heterocycloalkyl andheteroaryl rings can have from 5 to 6 ring members and from 1 to 4heteroatoms which can each independently be N, O or S. In someembodiments, ring J can be heterocycloalkyl, aryl or heteroaryl.Suitable heterocycloalkyl groups include those defined in thedefinitions above. In some embodiments, the heterocycloalkyl cantetrahydrofuran. Suitable aryl groups for ring J include those definedin the definitions above. Representative aryl groups include phenyl andnaphthyl. In some embodiments, the aryl group of ring J can be phenyl.Suitable heteroaryl groups for ring J include those defined in thedefinitions above. Representative heteroaryl groups include pyrrole,pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine,pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers),thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In someembodiments, the heteroaryl can be pyridyl or thiophene. In someembodiments, ring J can be aryl or heteroaryl. In some embodiments, ringJ can be phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole,thiadiazole, isothiazole, isoxazole, cyclohexyl, tetrahydrofuran andtetrahydro-2H-pyran. In some embodiments, ring J can be phenyl,pyridine, or pyrazole. In some embodiments, ring J can betetrahydrofuran, phenyl, pyridyl or thiophene. In some embodiments, ringJ can be phenyl. In some embodiments, ring J can be pyridyl. In someembodiments, ring J can be pyrazole.

In some embodiments, the heteroaryl of R¹ can be 3-pyrazole, 4-pyrazole,2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole,1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, 4-pyridine, pyrazine, or 2-pyrimidine, and RingJ can be 2-pyridine, 3-pyridine, 4-pyridine, imidazol-2-yl,imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, isoxazol-4-yl, cyclohexyl,tetrahydrofuran or tetrahydro-2H-pyran.

Ring J of formula I can be substituted with any suitable number of R²groups. Each R² of formula I can independently be hydrogen, C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, orC₃₋₈ heterocycloalkyl, wherein the heterocycloalkyl groups areoptionally substituted with 1-4 R^(2′) groups. In some embodiments, eachR² of formula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—NR^(2a)R^(2b), —C(O)OR^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, or C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl group has 5-6 ringmembers and 1 to 2 heteroatoms. In some embodiments, each R² of formulaI can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—NR^(2a)R^(2b), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl group has 5-6 ring members and 1 to 2heteroatoms. Each R² of formula I can independently be hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN,—NR^(2a)R^(2b), C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl, wherein theheterocycloalkyl groups are optionally substituted with 1-4 R^(2c)groups. In some embodiments, each R² can independently be hydrogen,halogen, C₁₋₆ haloalkyl, —CN, or heterocycloalkyl having 5-6 ringmembers and 1 to 2 heteroatoms wherein at least one heteroatom is N.Heterocycloalkyl groups having 5-6 ring members and 1 to 2 heteroatomswith at least one nitrogen include, but are not limited to, pyrrolidine,piperidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and1,4-isomers), oxazolidine, isoxalidine, thiazolidine, isothiazolidine,morpholine, or thiomorpholine. In some embodiments, each R² canindependently be hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl,—CF₃, CH₂OMe, OMe, OCHF₂, —CN, —NMe₂, —C(O)OH, —C(O)NMe₂, —S(O)₂Me,pyrrolidine, piperidine or morpholine. In some embodiments, each R² canindependently be hydrogen, methyl, ethyl, F, Cl, —CF₃, OMe, OCHF₂, —CN,—NMe₂, —S(O)₂Me, pyrrolidine, piperidine or morpholine. In someembodiments, each R² can independently be hydrogen, F, —CF₃, —CN,pyrrolidine, piperidine or morpholine. In some embodiments, R² can be—CF₃. Ring J can be substituted with 1, 2, 3 or 4 R² groups. In someembodiments, ring J is substituted with 1 R² group.

Several R² groups can be further substituted with one or more of R^(2a),R^(2b) and R^(2c). R^(2a) and R^(2b) can each independently be hydrogenor C₁₋₆ alkyl. Each R^(2c) can independently be hydrogen, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN, or —NR^(2a)R^(2b).

R³ of formula I can be phenyl or pyridyl, each optionally substitutedwith 1-4 Ria groups. In some embodiments, R³ can be substituted with 1R^(3a) group. Each R^(3a) group can independently be hydrogen, halogen,or C₁₋₆ haloalkyl. In some embodiments, each R^(3a) group canindependently be H, F, Cl, Br, or —CF₃. In some embodiments, each R^(3a)group can independently be F or —CF₃. In some embodiments, R^(3a) can beF. The R^(3a) group can be present at any position on the phenyl orpyridyl ring to form a 2-, 3- or 4-substituted ring. In someembodiments, the phenyl or pyridyl ring is substituted at the4-position. In some embodiments, R³ can be 4-F-phenyl.

When R³ of formula I is 4-F-phenyl, the compounds of the presentinvention can have the following structure:

Alternatively, the compounds of the present invention can have thefollowing structure:

Subscript n of formula I can be an integer from 0 to 3. In someembodiments, subscript n can be 0, 1, 2, or 3. In some embodiments,subscript n can be 0 or 1. In some embodiments, subscript n can be 0. Insome embodiments, subscript n can be 1.

In some embodiments, the compound of formula I can be:

-   Intermediate 13.    (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Intermediate 14.    (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 1.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 1A.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone,-   Example 1B.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)methanone,-   Example 1C.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 1D.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone,-   Example 1E.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)methanone,-   Example 1F.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone,-   Example 1G.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)methanone,-   Example 1H.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiophen-2-yl)methanone,-   Example 1I.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone,-   Example 1J.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanone,-   Example 1K.    (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone,-   Example 1L.    (R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone,-   Example 1M.    (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone,-   Example 2.    (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2A.    (R)-(6-((3-fluorobenzyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 2B.    ((4aR)-1-(4-fluorophenyl)-6-((((R/S)-tetrahydrofuran-2-yl)methyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 2C.    (R)-(1-(4-fluorophenyl)-6-(o-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2D.    (R)-(6-((4-ethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2E.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2F.    (R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2G.    (R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2H.    (R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2I.    (R)-(1-(4-fluorophenyl)-6-((4-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2J.    (R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2K.    (R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2L.    (R)-(1-(4-fluorophenyl)-6-((2-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2M.    (R)-(1-(4-fluorophenyl)-6-((l-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2N.    (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2O.    (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2P.    (R)-(6((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2Q.    (R)-4-(1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   Example 2R.    (R)-(1-(4-fluorophenyl)-6-((6-methoxypyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2S.    (R)-(1-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2T.    (R)-(6-(cyclohexylsulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 2U.    (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 2V.    (R)-(6-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 2W.    (R)-(6-((1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 3.    (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 4.    (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 5.    (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 5A.    (R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 5B.    (R)-4-(((1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)methyl)benzonitrile,-   Example 5C.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 5D.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-1,2,4-triazol-5-yl)methanone,-   Example 5E.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrazin-2-yl)methanone,-   Example 5F.    (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 5G.    (R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 5H.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methoxypyridin-2-yl)methanone,-   Example 5I.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-5-yl)methanone,-   Example 5J.    (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 6.    (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 6A.    (R)-(1-(4-fluorophenyl)-6-((3-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 7.    (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 7A.    (R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 8.    (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 9.    ((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 10.    (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 10A.    (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 10B.    (R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11A.    (R)-(6-((4-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11B.    (R)-(1-(4-fluorophenyl)-6-((4-methoxy-3-methylphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11C.    (R)-(6-((3-chloro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11D.    (R)-(6-((3-fluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11E.    (R)-(6-((2-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11F.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11G.    (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   Example 11H.    (R)-(6-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11I.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11J.    (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11K.    (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11L.    (R)-(6-((3-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11M.    (R)-(6-((3,4-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11N.    (R)-(6-((3,5-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11O.    (R)-(1-(4-fluorophenyl)-6-((6-methylpyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11P.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11Q.    (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11R.    (R)-(6-((3-chloro-4-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11S.    (R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   Example 11T.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11U.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11V.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11W.    (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11X.    (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11Y.    (R)-(1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11Z.    (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic    acid,-   Example 11AA.    (R)-(1-(4-fluorophenyl)-6-((3-(methoxymethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AB.    (R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AC.    (R)-(1-(4-fluorophenyl)-6-((2,3,4-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AD.    (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AE.    (R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AF.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AG.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AH.    (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11A.    (R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AJ.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AK.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AL.    (R)-(6-((4-fluoro-3-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AM.    (R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AN.    (R)-(6-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AO.    (R)-5-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylindolin-2-one,-   Example 11AP.    (R)-(1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AQ.    (R)-(6-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AR.    (R)-(6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AS.    (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AT.    (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AU.    (R)-3-((4a-(4-ethylpicolinoyl)-1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   Example 11AV.    (R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone,-   Example 11AW.    (R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoic    acid,-   Example 11AX.    (R)-(6-((3,5-dimethylisoxazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11AY.    (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11AZ.    (R)-(1-phenyl-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BA.    (R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11BB.    (R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11BC.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11BD.    (R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 11BE.    (R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BF.    (R)-(6-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BG.    (R)-(6-((3-chloro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BH.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(2-(pyrrolidin-1-yl)pyridin-4-yl)methanone,-   Example 11BI.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BJ.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BK.    (R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BL.    (R)-3-((1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   Example 11BM.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BN.    (R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BO.    (R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BP.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BQ.    (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BR.    (R)-(1-(4-chlorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BS.    (R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BT.    (R)-(6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1-(4-(trifluoromethyl)phenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11BU.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11BV.    (R)-(6-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BW.    (R)-(6-((1,2-dimethyl-1H-imidazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BX.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BY.    (R)-(6-((1-ethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11BZ.    (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CA.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CB.    (R)-(1-(4-fluorophenyl)-6-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CC.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-pyrazol-4-yl)methanone,-   Example 11CD.    (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CE.    (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CF.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CG.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CH.    (R)-(6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CI.    (R)-(6-((1-ethyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CJ.    (R)-(6-((1-ethyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CK.    (R)-(6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CL.    (R)-(6-((1-ethyl-1H-1,2,3-triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CM.    (R)-(6-((1-ethyl-1H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CN.    (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CO.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CP.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CQ.    (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CR.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CS.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CT.    (R)-(1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CU.    (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CV.    (R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 11CW.    (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CX.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 11CY.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 11CZ.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   Example 12.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12A.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12B.    (R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12C.    (R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12D.    (R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12E.    (R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12F.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylpyridin-2-yl)methanone,-   Example 12G.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   Example 12H.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(6-methylpyridin-2-yl)methanone,-   Example 12I.    (R)-(6-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12J.    (R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12K.    (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12L.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12M.    (R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylthiazol-2-yl)methanone,-   Example 12N.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12O.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12P.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12Q.    (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12R.    (R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12S.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12T.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12U.    (R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12V.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   Example 12W.    (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12X.    (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 12Y.    (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   Example 13.    (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone,-   Example 13A.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone,-   Example 14.    (R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide,-   Example 15.    (R)-(6-((1-ethyl-H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 15A.    (R)-pyridin-2-yl(1-(pyridin-3-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone,-   Example 15B.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-phenyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 15C.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(3,4-difluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 15D.    (R)-(6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 16.    (R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   Example 17.    (R)-5-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylpyridin-2(1H)-one,-   Example 18.    (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   Example 19.    (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,    or salts and isomers thereof.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,    or-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,    or-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,    or-   (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,    or-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,    or-   (R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone.

In some embodiments, the compound of formula I can be

-   (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   (R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone,-   (R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   (R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,    or-   (R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.

The compounds of the present invention can also include compounds offormula II:

wherein R¹, R², R³, ring J and subscript n are as described above.

When R³ of formula II is 4-F-phenyl, the compounds of formula II canhave the following structure:

Alternatively, the compounds of formula II can have the followingstructure:

In some embodiments, the compound of formula II can be

-   Intermediate 3.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol,-   Intermediate 4.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)-(R/S)-methanol,-   Intermediate 5.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanol,-   Intermediate 6.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)-(R/S)-methanol,-   Intermediate 7.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)-(R/S)-methanol,-   Intermediate 8.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)-(R/S)-methanol,-   Intermediate 9.    (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiophen-2-yl)-(R/S)-methanol,-   Intermediate 15.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)-(R/S)-methanol,-   Intermediate 16.    (R)-(1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol,-   Intermediate 17.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol,-   Intermediate 18.    (R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)-(R/S)-methanol,-   Intermediate 19.    (R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)-(R/S)-methanol,-   Intermediate 20.    (R)-(1-(4-fluorophenyl)-6-(3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)-(R/S)-methanol,    or-   Intermediate 62.    (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)-(R/S)-methanol.    Compounds of Formula II

(II)

Inter- mediate Com- pound R¹ R^(1a) Ring J R² n R³  3 pyridin-2-ylphenyl 4-CF₃ 0 4-F-phenyl  4 pyridin-3-yl phenyl 4-CF₃ 0 4-F-phenyl  51H-imidazol- 1-Me phenyl 4-CF₃ 0 4-F-phenyl 2-yl  6 thiazol-2-yl phenyl4-CF₃ 0 4-F-phenyl  7 oxazol-4-yl phenyl 4-CF₃ 0 4-F-phenyl  8furan-2-yl phenyl 4-CF₃ 0 4-F-phenyl  9 thiophen-2-yl phenyl 4-CF₃ 04-F-phenyl 15 1,3,4- 5-Me phenyl 4-CF₃ 0 4-F-phenyl oxadiazol-2-yl 16oxazol-2-yl phenyl 4-CF₃ 0 4-F-phenyl 17 oxazol-2-yl phenyl 3-Me 04-F-phenyl 18 pyridin-2-yl 4-OMe phenyl 3,5-difluoro 0 4-F-phenyl 19pyridin-2-yl 4-Et phenyl 3,4,5- 0 4-F-phenyl trifluoro 20 pyridin-2-yl4-OMe phenyl 3,4,5- 0 4-F-phenyl trifluoro 62 pyrimidin-2-yl phenyl 3-Me0 4-F-phenyl

The compounds of the present invention can also be the salts and isomersthereof. In some embodiments, the compounds of the present inventioninclude the salt forms thereof. Examples of applicable salt formsinclude hydrochlorides, hydrobromides, sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.(+)-tartrates, (−)-tartrates or mixtures thereof including racemicmixtures), succinates, benzoates and salts with amino acids such asglutamic acid. These salts may be prepared by methods known to thoseskilled in art. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of acceptable acid addition salts include those derived frominorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromorganic acids like acetic, propionic, isobutyric, maleic, malonic,benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, andthe like. Also included are salts of amino acids such as arginate andthe like, and salts of organic acids like glucuronic or galactunoricacids and the like (see, for example, Berge et al., “PharmaceuticalSalts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certainspecific compounds of the present invention contain basic acidicfunctionalities that allow the compounds to be converted into baseaddition salts. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the enantiomers, racemates,diastereomers, tautomers, geometric isomers, stereoisometric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques.

Isomers include compounds having the same number and kind of atoms, andhence the same molecular weight, but differing in respect to thestructural arrangement or configuration of the atoms.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention. Tautomerrefers to one of two or more structural isomers which exist inequilibrium and which are readily converted from one isomeric form toanother.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, the compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds of thepresent invention may be radiolabeled with radioactive isotopes, such asfor example deuterium (²H), tritium (³H), iodine-125 (¹²⁵I), carbon-13(¹³C), or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

The compounds of the invention can be synthesized by a variety ofmethods known to one of skill in the art (see Comprehensive OrganicTransformations Richard C. Larock, 1989) or by an appropriatecombination of generally well known synthetic methods. Techniques usefulin synthesizing the compounds of the invention are both readily apparentand accessible to those of skill in the relevant art. The discussionbelow is offered to illustrate certain of the diverse methods availablefor use in assembling the compounds of the invention. However, thediscussion is not intended to define the scope of reactions or reactionsequences that are useful in preparing the compounds of the presentinvention. One of skill in the art will appreciate that other methods ofmaking the compounds are useful in the present invention. Although somecompounds in FIG. 1 , FIG. 2 , and Table 1 may indicate relativestereochemistry, the compounds may exist as a racemic mixture or aseither enantiomer.

Compounds of the present invention can be prepared as shown in FIG. 1 .Starting materials can be obtained from commercial sources, by employingknown synthetic methods, and by employing methods described in U.S. Pat.No. 7,928,237, incorporated herein by reference. Esters I are convertedto ketones IV by reaction with an appropriate organometallic reagentsuch as a Grignard reagent, an organolithium reagent, an organoboronreagent, an organocerium reagent or an organozinc reagent in a solventsuch as ether or tetrahydrofuran, or a similar aprotic solvent. Ketonesof formula IV are also prepared by reaction of an aldehyde of formula IIwith an appropriate organometallic reagent followed by oxidation of theresultant alcohols of formula III with a suitable oxidizing agent suchas the Dess-Martin periodindane reagent in an inert solvent such asdichloromethane. The tert-butoxycarbonyl protecting group is removedfrom IV by treatment with an acid, such as HCl, HBr, trifluoroaceticacid, p-toluenesulfonic acid or methanesulfonic acid, preferably HCl ortrifluoroacetic acid, optionally in a solvent such as dioxane, ethanolor tetrahydrofuran, preferably dioxane, either under anhydrous oraqueous conditions. Amines V are converted to the compounds of formula(1) by treatment with an appropriate substituted sulfonyl halide, suchas the sulfonyl chloride VI, in an inert solvent such asdichloromethane, toluene or tetrahydrofuran, preferably dichloromethane,in the presence of a base such as N,N-di-isopropylethylamine ortriethylamine. It may be convenient to carry out the sulfonylationreaction in situ, without isolation of the amine V. Compounds of formula(1) can also be prepared from amines of formula V in a two-step sequencebeginning with reaction of amines V with a halo-substituted sulfonylchloride, VII, to afford a halo-substituted sulfonamide derivativeexemplified by VIII (in which X represents a halogen). The halogensubstituent X can be converted in a substituent R² by any standardmethod known to those skilled in the art. For example, if R² representsan amino substituent NR′R″ (in which NR′R″ can be either an acyclic orcyclic amine), this can be introduced by treating a compound of formulaVIII with an amine HNR′R″ in an inert solvent, such as tetrahydrofuran,toluene or N,N-dimethylformamide, in the presence of a palladiumcatalyst (e.g. BINAP/Pd₂(dba)₃) and a base (e.g. sodium or potassiumtert-butoxide), optionally under microwave conditions, to affordcompounds of formula (1). Alternatively, if X represents a fluorine orchlorine and R² represents an amino substituent NR′R″, R² may beintroduced by direct nucleophilic displacement of X. This may beaccomplished using any standard method known to those skilled in theart, such as by reacting a compound of formula VIII with an amine,optionally at elevated temperature, optionally under microwaveconditions, optionally in an appropriate solvent such as acetonitrile orN-methylpyrrolidine.

Alternatively, compounds of formula (1) are prepared as shown FIG. 2 .The tert-butoxycarbonyl protecting group is removed from I by treatmentwith an acid, such as HCl, HBr, trifluoroacetic acid, p-toluenesulfonicacid or methanesulfonic acid, preferably HCl or trifluoroacetic acid,optionally in a solvent such as dioxane, ethanol or tetrahydrofuran,preferably dioxane, either under anhydrous or aqueous conditions. AminesIX are converted to the sulfonamides of formula X as described for theconversion of amines of formula V into sulfonamides of formula (1). Theester group in compounds of formula X is converted to an aldehyde offormula XI by using a reducing agent such as DIBAL-H, LiAlH₄ or RED-AL,preferably DIBAL-H in an inert solvent such as dichloromethane,tetrahydrofuran, benzene or toluene, preferably dichloromethane. It maybe convenient to convert X into XI using a two-step process involvingreduction of the ester to an alcohol and subsequent oxidation of thealcohol to an aldehyde of formula XI. The oxidation can be carried outusing any suitable procedure, such as the Swern reaction, or anoxidizing reagent such as the Dess-Martin periodindane reagent in asuitable solvent, such as dichloromethane. Aldehydes of formula XI areconverted into alcohols of formula XII using a suitable organometallicreagent, such as a Grignard reagent, an organolithium reagent, anorganoboron reagent, an organocerium reagent or an organozinc reagent.Alcohols of formula XII are converted into ketones of formula (1) byoxidation. Suitable oxidation conditions include the Swern reaction andthe use of the Dess-Martin periodinane reagent. Alternatively, esters offormula X are converted directly to ketones of formula (1) using anappropriate organometallic reagent.

IV. Pharmaceutical Compositions

In some embodiments, the present invention provides a pharmaceuticalcomposition including a pharmaceutically acceptable excipient and acompound of the present invention. In some embodiments, the compositionalso includes an anti-inflammatory glucocorticosteroid.

Anti-Inflammatory Glucocorticosteroids

Anti-inflammatory glucocorticosteroids suitable for use with the presentinvention include those glucocorticosteroids that bind GR and include,but are not limited to, alclometasone, alclometasone dipropioate,beclometasone, beclometasone dipropionate, betamethasone, betamethasonebutyrate proprionate, betamethasone dipropionate, betamethasonevalerate, budesonide, ciclesonide, clobetasol, clobetasol propionate,clocortolone, clocortolone pivalate, cortexolone, cortisol, cortisporin,cortivazol, deflazacort, deprodone, deprodone propionate, desonide,dexamethasone, dexamethasone acetate, dexamethasone cipecilate,dexamethasone palmitate, difluprednate, fludroxycortide, flunisolide,fluocinolone, fluocinolone acetonide, fluocinonide, fluocortolone,fluorometholone, fluticasone, fluticasone propionate, fluticasonefuroate, halcinonide, halometasone, halopredone, halopredone acetate,hydrocortisone, hydrocortisone 17-butyrate, hydrocortisone aceponate,hydrocortisone acetate, hydrocortisone probutate, hydrocortisone sodiumsuccinate, loteprednol, loteprednol etabonate, meprednisone,methylprednisolone, methylprednisolone aceponate, methylprednisolonesuleptanate, mometasone, mometasone furoate, naflocort,19-nordeoxycorticosterone, 19-norprogesterone, otobiotic, oxazacort,paramethasone, prednicarbate, prednisolone, prednisolone farnesylate,prednisone, prednisone sodium phosphate, prednylidene, proctosedyl,rimexolone, tobradex, triamcinolone, triamcinolone hexacetonide,trimexolone, ulobetasol, ulobetasol propionate,11β-(4-dimethylaminoethoxyphenyl)-17a-propynyl-17β-hydroxy-4,9estradien-3-one(RU009), 17β-hydroxy-17a-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one(RU044), and the salt and esters forms thereof.

Additional anti-inflammatory glucocorticosteroids suitable for use withthe present invention include, but are not limited to, a naturallyoccurring or synthetic steroid glucocorticoid which can be derived fromcholesterol and is characterized by a hydrogenatedcyclopentanoperhydrophenanthrene ring system. Suitableglucocorticosteroids also include, but are not limited to,11-alpha,17-alpha,21-trihydroxypregn-4-ene-3,20-dione;11-beta,16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione;11-beta,16-alpha,17,21-tetrahydroxypregn-1,4-diene-3,20-dione;11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione;11-dehydrocorticosterone; 11-deoxycortisol;11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone;14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone;16-methylhydrocortisone;17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione;17-alpha-hydroxypregn-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone;17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione;17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione;17-hydroxypregna-4,9(11)-diene-3,20-dione; 18-hydroxycorticosterone;18-hydroxycortisone; 18-oxocortisol; 21-acetoxypregnenolone;21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone;2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-beta,21-triol-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one;6-alpha-hydroxycortisol; 6-alphafluoroprednisolone;6-alpha-methylprednisolone; 6-alpha-methylprednisolone-21-acetate;6-alpha-methylprednisolone 21-hemi succinate sodium salt, 6-betahydroxycortisol, 6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate,6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednisolone;9-fluorocortisone; alclomethasone dipropionate; algestone; alphaderm;amadinone; amcinonide; anagestone; androstenedione; anecortave acetate;beclomethasone; beclomethasone dipropionate; betamethasone 17-valerate;betamethasone sodium acetate; betamethasone sodium phosphate;betamethasone valerate; bolasterone; budesonide; calusterone;chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol;ciclesonide; clobetasol; clobetasol propionate; clobetasone;clocortolone; clocortolone pivalate; clogestone; cloprednol;corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisolcypionate; cortisol octanoate; cortisol sodium phosphate; cortisolsodium succinate; cortisol valerate; cortisone; cortisone acetate;cortivazol; cortodoxone; daturaolone; deflazacort, 21-deoxycortisol,dehydroepiandrosterone; delmadinone; deoxycorticosterone; deprodone;descinolone; desonide; desoximethasone; dexafen; dexamethasone;dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodiumphosphate; dichlorisone; diflorasone; diflorasone diacetate;diflucortolone; difluprednate; dihydroelatericin a; domoprednate;doxibetasol; ecdysone; ecdysterone; emoxolone; endrysone; enoxolone;fluazacort; flucinolone; flucloronide; fludrocortisone; fludrocortisoneacetate; flugestone; flumethasone; flumethasone pivalate; flumoxonide;flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide;fluocortin butyl; 9-fluorocortisone; fluocortolone;fluorohydroxyandrostenedione; fluorometholone; fluorometholone acetate;fluoxymesterone; fluperolone acetate; fluprednidene; fluprednisolone;flurandrenolide; fluticasone; fluticasone propionate; fonnebolone;fonnestane; fonnocortal; gestonorone; glyderinine; halcinonide;halobetasol propionate; halometasone; halopredone; haloprogesterone;hydrocortamate; hydrocortiosone cypionate; hydrocortisone;hydrocortisone; 21-butyrate; hydrocortisone aceponate; hydrocortisoneacetate; hydrocortisone buteprate; hydrocortisone butyrate;hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisoneprobutate; hydrocortisone sodium phosphate; hydrocortisone sodiumsuccinate; hydrocortisone valerate; hydroxyprogesterone; inokosterone;isoflupredone; isoflupredone acetate; isoprednidene; loteprednoletabonate; meclorisone; mecortolon; medrogestone; medroxyprogesterone;medrysone; megestrol; megestrol acetate; melengestrol; meprednisone;methandrostenolone; methylprednisolone; methylprednisolone aceponate;methylprednisolone acetate; methylprednisolone hemisuccinate;methylprednisolone sodium succinate; methyltestosterone; metribolone;mometasone; mometasone furoate; mometasone furoate monohydrate; nisone;nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone;paramethasone acetate; ponasterone; prednicarbate; prednisolamate;prednisolone; prednisolone 21-diethylaminoacetate; prednisolone21-hemisuccinate; prednisolone acetate; prednisolone famesylate;prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide);prednisolone metasulphobenzoate; prednisolone sodium phosphate;prednisolone steaglate; prednisolone tebutate; prednisolonetetrahydrophthalate; prednisone; prednival; prednylidene; pregnenolone;

procinonide; tralonide; progesterone; promegestone; rhapontisterone;rimexolone; roxibolone; rubrosterone; stizophyllin; tixocortol;topterone; triamcinolone; triamcinolone acetonide; triamcinoloneacetonide 21-palmitate; triamcinolone benetonide; triamcinolonediacetate; triamcinolone hexacetonide; trimegestone; turkesterone; andwortmannin.

Additional anti-inflammatory glucocorticosteroids suitable for use withthe present invention include, but are not limited to, alclometasone,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,clocortolone, cortexolone, cortisol, cortisporin, cortivazol,deflazacort, deprodone, desonide, dexamethasone, difluprednate,fludroxycortide, flunisolide, fluocinolone, fluocinonide, fluocortolone,fluorometholone, fluticasone, halcinonide, halometasone, halopredone,hydrocortisone, loteprednol, meprednisone, methylprednisolone,mometasone, naflocort, 19-nordeoxycorticosterone, 19-norprogesterone,otobiotic, oxazacort, paramethasone, prednicarbate, prednisolone,prednisone, prednylidene, proctosedyl, rimexolone, tobradex,triamcinolone, trimexolone, ulobetasol,11β-(4-dimethylaminoethoxyphenyl)-17a-propynyl-17β-hydroxy-4,9estradien-3-one (RU009), and17β-hydroxy-17a-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one (RU044).

The anti-inflammatory glucocorticosteroids of the present invention alsoinclude the salts, hydrates, solvates and prodrug forms. Theanti-inflammatory glucocorticosteroids of the present invention alsoinclude the isomers and metabolites of those described above.

Salts include, but are not limited, to sulfate, citrate, acetate,oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, phosphonic acid, isonicotinate, lactate, salicylate, citrate,tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Other saltsinclude, but are not limited to, salts with inorganic bases includingalkali metal salts such as sodium salts, and potassium salts; alkalineearth metal salts such as calcium salts, and magnesium salts; aluminumsalts; and ammonium salts. Other salts with organic bases include saltswith diethylamine, diethanolamine, meglumine, andN,N′-dibenzylethylenediamine.

The neutral forms of the anti-inflammatory glucocorticosteroids can beregenerated by contacting the salt with a base or acid and isolating theparent anti-inflammatory glucocorticosteroid in the conventional manner.The parent form of the anti-inflammatory glucocorticosteroid differsfrom the various salt forms in certain physical properties, such assolubility in polar solvents, but otherwise the salts are equivalent tothe parent form of the compound for the purposes of the presentinvention.

Certain anti-inflammatory glucocorticosteroids of the present inventioncan exist in unsolvated forms as well as solvated forms, includinghydrated forms. In general, the solvated forms are equivalent tounsolvated forms and are encompassed within the scope of the presentinvention. Certain anti-inflammatory glucocorticosteroids of the presentinvention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe present invention and are intended to be within the scope of thepresent invention.

Certain anti-inflammatory glucocorticosteroids of the present inventionpossess asymmetric carbon atoms (optical centers) or double bonds; theenantiomers, racemates, diastereomers, tautomers, geometric isomers,stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids,and individual isomers are encompassed within the scope of the presentinvention. The anti-inflammatory glucocorticosteroids of the presentinvention do not include those which are known in art to be too unstableto synthesize and/or isolate. The present invention is meant to includeanti-inflammatory glucocorticosteroids in racemic and optically pureforms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques.

The present invention also provides anti-inflammatoryglucocorticosteroids which are in a prodrug form. Prodrugs of theanti-inflammatory glucocorticosteroids described herein are thoseanti-inflammatory glucocorticosteroids that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to theanti-inflammatory glucocorticosteroids of the present invention bychemical or biochemical methods in an ex vivo environment. For example,prodrugs can be slowly converted to the anti-inflammatoryglucocorticosteroids of the present invention when placed in atransdermal patch reservoir with a suitable enzyme or chemical reagent.

V. Formulation

The compositions of the present invention can be prepared in a widevariety of oral, parenteral and topical dosage forms. Oral preparationsinclude tablets, pills, powder, dragees, capsules, liquids, lozenges,cachets, gels, syrups, slurries, suspensions, etc., suitable foringestion by the patient. The compositions of the present invention canalso be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compositions described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompositions of the present invention can be administered transdermally.The compositions of this invention can also be administered byintraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995). Accordingly, the present invention also provides pharmaceuticalcompositions including a pharmaceutically acceptable carrier orexcipient and a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of the compounds of the present invention.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain thecompounds of the present invention mixed with a filler or binders suchas lactose or starches, lubricants such as talc or magnesium stearate,and, optionally, stabilizers. In soft capsules, the compounds of thepresent invention may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycol withor without stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the compoundsof the present invention are dispersed homogeneously therein, as bystirring. The molten homogeneous mixture is then poured into convenientsized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe compounds of the present invention in water and adding suitablecolorants, flavors, stabilizers, and thickening agents as desired.Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partialester derived from a fatty acid and a hexitol (e.g., polyoxyethylenesorbitol mono-oleate), or a condensation product of ethylene oxide witha partial ester derived from fatty acid and a hexitol anhydride (e.g.,polyoxyethylene sorbitan mono-oleate). The aqueous suspension can alsocontain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose, aspartame orsaccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending the compounds of thepresent invention in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin;or a mixture of these. The oil suspensions can contain a thickeningagent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteningagents can be added to provide a palatable oral preparation, such asglycerol, sorbitol or sucrose. These formulations can be preserved bythe addition of an antioxidant such as ascorbic acid. As an example ofan injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of the invention canalso be in the form of oil-in-water emulsions. The oily phase can be avegetable oil or a mineral oil, described above, or a mixture of these.

Suitable emulsifying agents include naturally-occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The compositions of the present invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe formulated for administration via intradermal injection ofdrug-containing microspheres, which slowly release subcutaneously (seeRao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable andinjectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months.

In another embodiment, the compositions of the present invention can beformulated for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

Lipid-based drug delivery systems include lipid solutions, lipidemulsions, lipid dispersions, self-emulsifying drug delivery systems(SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). Inparticular, SEDDS and SMEDDS are isotropic mixtures of lipids,surfactants and co-surfactants that can disperse spontaneously inaqueous media and form fine emulsions (SEDDS) or microemulsions(SMEDDS). Lipids useful in the formulations of the present inventioninclude any natural or synthetic lipids including, but not limited to,sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters,glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®,Capryol®, Capmul®, Captex®, and Peceol®.

VI. Administration

The compounds and compositions of the present invention can be deliveredby any suitable means, including oral, parenteral and topical methods.Transdermal administration methods, by a topical route, can beformulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the compounds and compositions of the presentinvention. The unit dosage form can be a packaged preparation, thepackage containing discrete quantities of preparation, such as packetedtablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

The compounds and compositions of the present invention can beco-administered with other agents. Co-administration includesadministering the compound or composition of the present inventionwithin 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the otheragent. Co-administration also includes administering simultaneously,approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30minutes of each other), or sequentially in any order. Moreover, thecompounds and compositions of the present invention can each beadministered once a day, or two, three, or more times per day so as toprovide the preferred dosage level per day.

In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding the compounds and compositions of the present invention andany other agent. Alternatively, the various components can be formulatedseparately.

The compounds and compositions of the present invention, and any otheragents, can be present in any suitable amount, and can depend on variousfactors including, but not limited to, weight and age of the subject,state of the disease, etc. Suitable dosage ranges include from about 0.1mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg toabout 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50,60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.

The composition can also contain other compatible therapeutic agents.The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in modulating aglucocorticoid receptor, or with adjunctive agents that may not beeffective alone, but may contribute to the efficacy of the active agent.

VII. Methods of Modulating a Glucocorticoid Receptor and Treating aDisorder

In some embodiments, the present invention provides a method ofmodulating a glucocorticoid receptor, the method including contacting aglucocorticoid receptor with a compound of the present invention,thereby modulating the glucocorticoid receptor.

In some embodiments, the present invention provides a method of treatinga disorder through modulating a glucocorticoid receptor, the methodincluding administering to a subject in need of such treatment, atherapeutically effective amount of a compound of the present invention,thereby treating the disorder.

In some other embodiments, the present invention provides a method oftreating a disorder through antagonizing a glucocorticoid receptor, themethod including administering to a subject in need of such treatment,an effective amount of the compound of the present invention, therebytreating the disorder.

In another embodiment, the present invention provides methods ofmodulating glucocorticoid receptor activity using the techniquesdescribed herein. In an exemplary embodiment, the method includescontacting a GR with an effective amount of a compound of the presentinvention, such as the compound of the present invention, and detectinga change in GR activity.

In an exemplary embodiment, the GR modulator is an antagonist of GRactivity (also referred to herein as “a glucocorticoid receptorantagonist”). A glucocorticoid receptor antagonist, as used herein,refers to any composition or compound which partially or completelyinhibits (antagonizes) the binding of a glucocorticoid receptor (GR)agonist (e.g. cortisol and synthetic or natural cortisol analog) to a GRthereby inhibiting any biological response associated with the bindingof a GR to the agonist.

In a related embodiment, the GR modulator is a specific glucocorticoidreceptor antagonist. As used herein, a specific glucocorticoid receptorantagonist refers to a composition or compound which inhibits anybiological response associated with the binding of a GR to an agonist bypreferentially binding to the GR rather than another nuclear receptor(NR). In some embodiments, the specific glucocorticoid receptorantagonist binds preferentially to GR rather than the mineralocorticoidreceptor (MR) or progesterone receptor (PR). In an exemplary embodiment,the specific glucocorticoid receptor antagonist binds preferentially toGR rather than the mineralocorticoid receptor (MR). In another exemplaryembodiment, the specific glucocorticoid receptor antagonist bindspreferentially to GR rather than the progesterone receptor (PR).

In a related embodiment, the specific glucocorticoid receptor antagonistbinds to the GR with an association constant (K_(d)) that is at least10-fold less than the K_(d) for other nuclear receptor. In anotherembodiment, the specific glucocorticoid receptor antagonist binds to theGR with an association constant (K_(d)) that is at least 100-fold lessthan the K_(d) for the other nuclear receptor. In another embodiment,the specific glucocorticoid receptor antagonist binds to the GR with anassociation constant (K_(d)) that is at least 1000-fold less than theK_(d) for the other nuclear receptor.

Examples of disorders or conditions suitable for use with presentinvention include, but are not limited to, obesity, diabetes,cardiovascular disease, hypertension, Syndrome X, depression, anxiety,glaucoma, human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer'sdisease, Parkinson's disease, cognition enhancement, Cushing's Syndrome,Addison's Disease, osteoporosis, frailty, muscle frailty, inflammatorydiseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis,adrenal function-related ailments, viral infection, immunodeficiency,immunomodulation, autoimmune diseases, allergies, wound healing,compulsive behavior, multi-drug resistance, addiction, psychosis,anorexia, cachexia, post-traumatic stress syndrome, post-surgical bonefracture, medical catabolism, major psychotic depression, mild cognitiveimpairment, psychosis, dementia, hyperglycemia, stress disorders,antipsychotic induced weight gain, delirium, cognitive impairment indepressed patients, cognitive deterioration in individuals with Down'ssyndrome, psychosis associated with interferon-alpha therapy, chronicpain, pain associated with gastroesophageal reflux disease, postpartumpsychosis, postpartum depression, neurological disorders in prematureinfants, and migraine headaches. In some embodiments, the disorder orcondition can be major psychotic depression, stress disorders orantipsychotic induced weight gain. In other embodiments, the disorder orcondition can be Cushing's Syndrome.

A. Binding Assays

GR modulators of this invention can be tested for binding activity in avariety of assays. For example, by screening for the ability to competewith a GR ligand, such as dexamethasone, for binding to theglucocorticoid receptor. Those of skill in the art will recognize thatthere are a number of ways to perform such competitive binding assays.In some embodiments, GR is pre-incubated with a labeled GR ligand andthen contacted with a test compound. This type of competitive bindingassay may also be referred to herein as a binding displacement assay.Alteration (e.g., a decrease) of the quantity of ligand bound to GRindicates that the molecule is a potential GR modulator. Alternatively,the binding of a test compound to GR can be measured directly with alabeled test compound. This latter type of assay is called a directbinding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a GR ligand and the binding agent can be GR boundto a solid phase. Alternatively, the labeled analyte can be labeled GRand the binding agent can be a solid phase GR ligand. The concentrationof labeled analyte bound to the capture agent is inversely proportionalto the ability of a test compound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in liquidphase, and any of a variety of techniques known in the art may be usedto separate the bound labeled protein from the unbound labeled protein.For example, several procedures have been developed for distinguishingbetween bound ligand and excess bound ligand or between bound testcompound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on the GR may bealtered by the binding of the GR to its ligand or test compound. Thisalteration in the labeled GR results in a decrease or increase in thesignal emitted by label, so that measurement of the label at the end ofthe binding assay allows for detection or quantitation of the GR in thebound state. A wide variety of labels may be used. The component may belabeled by any one of several methods. Useful radioactive labels includethose incorporating ³H, ¹²⁵, ³⁵S, ¹⁴C or ³²P. Useful non-radioactivelabels include those incorporating fluorophores, chemiluminescentagents, phosphorescent agents, electrochemiluminescent agents, and thelike. Fluorescent agents are especially useful in analytical techniquesthat are used to detect shifts in protein structure such as fluorescenceanisotropy and/or fluorescence polarization. The choice of label dependson sensitivity required, ease of conjugation with the compound,stability requirements, and available instrumentation. For a review ofvarious labeling or signal producing systems which may be used, see U.S.Pat. No. 4,391,904, which is incorporated herein by reference in itsentirety for all purposes. The label may be coupled directly orindirectly to the desired component of the assay according to methodswell known in the art.

High-throughput screening methods may be used to assay a large number ofpotential modulator compounds. Such “compound libraries” are thenscreened in one or more assays, as described herein, to identify thoselibrary members (particular chemical species or subclasses) that displaya desired characteristic activity. Preparation and screening of chemicallibraries is well known to those of skill in the art. Devices for thepreparation of chemical libraries are commercially available (see, e.g.,357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin,Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus,Millipore, Bedford, Mass.).

B. Cell-Based Assays

Cell-based assays involve whole cells or cell fractions containing GR toassay for binding or modulation of activity of GR by a compound of thepresent invention. Exemplary cell types that can be used according tothe methods of the invention include, e.g., any mammalian cellsincluding leukocytes such as neutrophils, monocytes, macrophages,eosinophils, basophils, mast cells, and lymphocytes, such as T cells andB cells, leukemias, Burkitt's lymphomas, tumor cells (including mousemammary tumor virus cells), endothelial cells, fibroblasts, cardiaccells, muscle cells, breast tumor cells, ovarian cancer carcinomas,cervical carcinomas, glioblastomas, liver cells, kidney cells, andneuronal cells, as well as fungal cells, including yeast. Cells can beprimary cells or tumor cells or other types of immortal cell lines. Ofcourse, GR can be expressed in cells that do not express an endogenousversion of GR.

In some cases, fragments of GR, as well as protein fusions, can be usedfor screening. When molecules that compete for binding with GR ligandsare desired, the GR fragments used are fragments capable of binding theligands (e.g., dexamethasone). Alternatively, any fragment of GR can beused as a target to identify molecules that bind GR. GR fragments caninclude any fragment of, e.g., at least 20, 30, 40, 50 amino acids up toa protein containing all but one amino acid of GR.

In some embodiments, signaling triggered by GR activation is used toidentify GR modulators. Signaling activity of GR can be determined inmany ways. For example, downstream molecular events can be monitored todetermine signaling activity. Downstream events include those activitiesor manifestations that occur as a result of stimulation of a GRreceptor. Exemplary downstream events useful in the functionalevaluation of transcriptional activation and antagonism in unalteredcells include upregulation of a number of glucocorticoid responseelement (GRE)-dependent genes (PEPCK, tyrosine amino transferase,aromatase). In addition, specific cell types susceptible to GRactivation may be used, such as osteocalcin expression in osteoblastswhich is downregulated by glucocorticoids; primary hepatocytes whichexhibit glucocorticoid mediated upregulation of PEPCK andglucose-6-phospahte (G-6-Pase)). GRE-mediated gene expression has alsobeen demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g. the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); LPS stimulated cytokine release,e.g., TNFα; or expression of genes regulated by NFkB or AP-1transcription factors in transfected cell-lines.

Typically, compounds that are tested in whole-cell assays are alsotested in a cytotoxicity assay. Cytotoxicity assays are used todetermine the extent to which a perceived modulating effect is due tonon-GR binding cellular effects. In an exemplary embodiment, thecytotoxicity assay includes contacting a constitutively active cell withthe test compound. Any decrease in cellular activity indicates acytotoxic effect.

C. Specificity

The compounds of the present invention may be subject to a specificityassay (also referred to herein as a selectivity assay). Typically,specificity assays include testing a compound that binds GR in vitro orin a cell-based assay for the degree of binding to non-GR proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. Binding may be tested against any appropriate non-GRprotein, including antibodies, receptors, enzymes, and the like. In anexemplary embodiment, the non-GR binding protein is a cell-surfacereceptor or nuclear receptor. In another exemplary embodiment, thenon-GR protein is a steroid receptor, such as estrogen receptor,progesterone receptor, androgen receptor, or mineralocorticoid receptor.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the invention may be combined with any one or more other features ofany other embodiment of the invention, without departing from the scopeof the invention. For example, the features of the GR modulatorcompounds are equally applicable to the methods of treating diseasestates and/or the pharmaceutical compositions described herein. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference in their entirety for all purposes.

VIII. Methods of Treating and Reducing Steroid Side Effects

The compounds and compositions of the present invention are useful in avariety of methods such as treating a disorder or condition or reducingthe side effects of glucocorticosteroid treatment.

In some embodiments, the present invention provides a method ofinhibiting glucocorticoid receptor (GR) induced transactivation withoutsubstantially inhibiting GR-induced transrepression, wherein the methodincludes contacting a GR with a composition including ananti-inflammatory glucocorticosteroid able to induce both GRtransactivation and GR transrepression, and a GR modulator of thepresent invention, in an amount sufficient to inhibit GR inducedtransactivation without substantially inhibiting GR-inducedtransrepression, thereby inhibiting GR induced transactivation withoutsubstantially inhibiting GR-induced transrepression. In someembodiments, the method of inhibiting glucocorticoid receptor (GR)induced transactivation without substantially inhibiting GR-inducedtransrepression, includes contacting the GR with a composition includingthe compound(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone.

For those GR modulators of the present invention that can inhibittransactivation, the compounds can inhibit transactivation when GRinduced transactivation of gene expression is reduced by at least about50%, relative to the level of gene expression observed in the absence ofthe GR modulator. For example, GR induced transactivation can beinhibited by at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96,97, 98 or 99%. In some embodiments, glucocorticoid receptor inducedtransactivation is inhibited by at least about 50%. In otherembodiments, glucocorticoid receptor induced transactivation isinhibited by at least about 65%. In some other embodiments,glucocorticoid receptor induced transactivation is inhibited by at leastabout 75%. In still other embodiments, glucocorticoid receptor inducedtransactivation is inhibited by at least about 85%. In yet otherembodiments, glucocorticoid receptor induced transactivation isinhibited by at least about 95%.

For those GR modulators of the present invention that can inhibittransactivation, some of the GR modulators may be able do so while notsubstantially inhibiting GR-induced transrepression activity. Forexample, GR-induced transrepression is considered not substantiallyinhibited when, in the presence of the composition of the presentinvention, the GR-induced transrepression activity is inhibited by lessthan about 75%, relative to the level of GR-induced transrepressionactivity in the absence of the GR modulator of the present invention.GR-induced transrepression is also considered not substantiallyinhibited when the GR-induced transrepression activity is inhibited byless than about 70, 60, 50, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2 or1%, relative to the level of GR-induced transrepression activity in theabsence of the GR modulator of the present invention. In someembodiments, GR-induced transrepression activity is inhibited by lessthan about 50%. In other embodiments, GR-induced transrepressionactivity is inhibited by less than about 25%. In some other embodiments,GR-induced transrepression activity is inhibited by less than about 10%.

In other embodiments, the ratio of percent inhibition of GR inducedtransactivation inhibition to percent inhibition of GR-inducedtransrepression inhibition can be from about 1000 to 1. For example, theratio of percent inhibition of GR induced transactivation inhibition topercent inhibition of GR-induced transrepression inhibition can be about1000, 500, 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10, 5, 4, 3, 2,or 1.

In some other embodiments, the GR induced transactivation is caused bythe anti-inflammatory glucocorticosteroid described above.

In some embodiments, the present invention provides a method of treatinga disorder or condition, including administering to a subject in needthereof, a therapeutically effective amount of a composition includingan anti-inflammatory glucocorticosteroid and a GR modulator of thepresent invention. In some other embodiments, the anti-inflammatoryglucocorticosteroid and GR modulator of the present invention modulatethe activity of a GR. The diseases and conditions include, among other,inflammatory conditions and autoimmune diseases. In some embodiments,the disorder or condition can be glaucoma, inflammatory diseases,rheumatoid arthritis, asthma and rhinitis, allergies and autoimmunediseases. Representative autoimmune disease include, but are not limitedto, obstructive airways disease, including conditions such as COPD,asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, infantileasthma), bronchitis, including bronchial asthma, systemic lupuserythematosus (SLE), multiple sclerosis, type I diabetes mellitus andcomplications associated therewith, atopic eczema (atopic dermatitis),contact dermatitis and further eczematous dermatitis, inflammatory boweldisease (e.g. Crohn's disease and ulcerative colitis), atherosclerosisand amyotrophic lateral sclerosis. Other autoimmune diseases includetissue and organ transplants, and allergies.

In some embodiments, the present invention provides a method of reducingthe side effects of glucocorticosteroid treatment, includingadministering to a subject in need thereof, a therapeutically effectiveamount of a composition including an anti-inflammatoryglucocorticosteroid and a GR modulator having the structure of thepresent invention. In some embodiments, the side effects ofglucocorticosteroid treatment can be weight gain, glaucoma, fluidretention, increased blood pressure, mood swings, cataracts, high bloodsugar, diabetes, infection, loss of calcium from bones, osteoporosis, ormenstrual irregularities. Additional side effects include musclewasting, fat redistribution, growth retardation and cushingoidappearance.

Other conditions that can be treated using the compounds of the presentinvention include alcohol dependence, symptoms of alcohol withdrawal,and cognitive deficits associated with excess alcohol consumption. Thecompounds of the present invention can also be used to treat cancer,such as cancer of the bone, breast, prostate, ovary, skin, brain,bladder, cervix, liver, lung, etc. Other cancers that can be treatedusing the compounds of the present invention include leukemia, lymphoma,neuroblastoma, among others. When administered for the treatment ofcancer, the compounds of the present invention can be administeredseparately or in combination with an antineoplastic agent such astaxanes, taxol, docetaxel, paclitaxel, actinomycin, anthracyclines,doxorubicin, daunorubicin, valrubicin, bleomycin, cisplatin, amongothers.

Assays to Identify GR Modulators

GR modulators of this invention can be tested for inhibition of GRinduced transactivation while not substantially inhibiting GR-inducedtransrepression in a variety of assays. GR modulators of the presentinvention that inhibit GR induced transactivation can be identified bymeasuring the amount of tyrosine amino transferase expressed in thepresence of the GR induced transactivation in a cell model (human liverhepatocytes). GR modulators useful in the present invention can be thosethat inhibit GR induced transactivation by at least about 50%.

Moreover, for the GR modulators of the present invention that inducetransactivation, some may be able to do so while not inhibiting theGR-induced transrepression activity by more than about 50%.Specifically, the compositions of the present invention that can inducetransactivation while not substantially inhibiting the GR-inducedtransrepression activity of dexamethasone with regard to LPS activatedTNFα release (NFκB responsive gene), can be identified using acell-based model (human peripheral blood mononuclear cells),dexamethasone can be administered to the cells and the release of TNFαcan be measured. After addition of the GR modulator of the presentinvention, the release of TNFα can be again measured and compared to theamount released in the absence of the GR modulator. A GR modulator ofthe present invention that does not substantially block the effect ofdexamethasone, does not substantially inhibit GR-inducedtransrepression.

IX. EXAMPLES

Structures are named according to standard IUPAC nomenclature using theCambridgeSoft ChemDraw naming package.

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova spectrometer (400 MHz) with a 5 mm inverse detection tripleresonance probe for detection of H1, C13 and P31 or a Bruker Avance DRXspectrometer (400 MHz) with a 5 mm inverse detection triple resonanceTXI probe, or a Bruker Avance III spectrometer (400 MHz).

Mass spectrometry (LCMS) experiments to determine retention times andassociated mass ions were performed using the following methods:

Method A: experiments were performed using a Waters Platform LCquadrupole mass spectrometer with positive and negative ion electrosprayand ELS/Diode array detection using a Phenomenex Luna 3 micron C18 (2)30×4.6 mm column and a 2 mL/minute flow rate. The solvent system was 95%water containing 0.1% formic acid (solvent A) and 5% acetonitrilecontaining 0.1% formic acid (solvent B) for the first 50 secondsfollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 4 minutes. The final solvent system was held constant for a further1 minute.

Method B: experiments were performed using a VG Platform II quadrupolemass spectrometer with a positive and negative ion electrospray andELS/Diode array detection using a Phenomenex Luna 3 micron C18 (2)30×4.6 mm column and a 2 mL/minute flow rate. The initial solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 30seconds followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 2 minutes.

Method C: experiments were performed using a Waters ZMD quadrupole massspectrometer with positive and negative ion electrospray and ELS/Diodearray detection using a Phenomenex Luna 3 micron C18 (2) 30×4.6 mmcolumn and a 2 mL/minute flow rate. The solvent system was 95% watercontaining 0.1% formic acid (solvent A) and 5% acetonitrile containing0.1% formic acid (solvent B) for the first 50 seconds followed by agradient up to 5% solvent A and 95% solvent B over the next 4 minutes.The final solvent system was held constant for a further 1 minute.

Method D: experiments were performed using a Waters Micromass ZQ2000quadrupole mass spectrometer linked to a Waters Acquity UPLC system witha PDA UV detector using an Acquity UPLC BEH C18 1.7 micron 100×2.1 mm,maintained at 40° C. The spectrometer has an electrospray sourceoperating in positive and negative ion mode. The initial solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for 0.4 minutesfollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 6.4 minutes.

Method E: experiments were performed using a Waters Micromass ZQ2000quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LCsystem with a DAD UV detector using a Higgins Clipeus 5 micron C18100×3.0 mm, maintained at 40° C. The spectrometer has an electrospraysource operating in positive and negative ion mode. The initial solventsystem was 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for 1.0 minutesfollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 15 minutes. The final solvent system was held constant for afurther 5 minutes.

Method F: experiments were performed using an Agilent Infinity 1260 LC6120 quadrupole mass spectrometer with positive and negative ionelectrospray and ELS/UV @ 254 nm detection using an Agilent ZorbaxExtend C18, Rapid Resolution HT 1.8 micron C18 30×4.6 mm column and a2.5 mL/minute flow rate. The initial solvent system was 95% watercontaining 0.1% formic acid (solvent A) and 5% acetonitrile containing0.1% formic acid (solvent B) ramping up to 5% solvent A and 95% solventB over the next 3.0 minutes, the flow rate was then increased to 4.5mL/minute and held for 0.5 minutes at 95% B. Over 0.1 minute thegradient was returned to 95% A and 5% B and 3.5 mL/minute and was heldat these conditions for 0.3 minutes; the final 0.1 minute resulted inthe return to the initial starting conditions, 95% A 5% B at 2.5mL/minute.

Intermediate 1.(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehydeand Intermediate 2.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol

A solution of (R)-methyl1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(2.12 g, 3.96 mmol) was dissolved in dry dichloromethane and cooled to−78° C. under nitrogen. A solution of diisobutylaluminium hydride (1.0 Min dichloromethane, 16 mmol, 16 mL) was added dropwise maintaining thereaction temperature at <−70° C. and the reaction mixture was stirred at−78° C. for 1 hour. The reaction mixture was treated with water (6 mL),stirred at −78° C. for 5 minutes then warmed to >0° C. over 15 minutes.Solid sodium bicarbonate (5.5 g) was added and the mixture stirredvigorously for 5 minutes. Excess sodium sulfate was added (˜20 g) andthe resultant mixture was stirred vigorously for a further 15 minutes.The solid materials were removed by filtration and rinsed with a littledichloromethane. The filtrate was concentrated under reduced pressureand the residue purified by column chromatography on silica gel elutingwith a mixture of ethyl acetate and cyclohexane (3:7 by volume) followedby ethyl acetate to afford(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehydeas a white foam (0.62 g). 1H NMR (400 MHz, CDCl₃): 9.48 (s, 1H); 7.93(d, J=8.2 Hz, 2H); 7.84 (d, J=8.3 Hz, 2H); 7.39-7.40 (m, 3H); 7.17 (t,J=8.5 Hz, 2H); 6.52 (d, J=2.5 Hz, 1H); 4.32 (d, J=12.3 Hz, 1H); 3.90 (brs, 1H); 3.14 (d, J=16.4 Hz, 1H); 2.65-2.80 (m, 1H); 2.51-2.52 (m, 4H)and (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanolas a white solid (1.0 g). 1H NMR (400 MHz, CDCl₃): δ 7.94 (d, J=8.2 Hz,2H); 7.83 (d, J=8.3 Hz, 2H); 7.40-7.41 (m, 3H); 7.14-7.15 (m, 2H); 6.31(d, J=2.4 Hz, 1H); 4.11-4.12 (m, 1H); 4.02 (dd, J=11.4, 5.9 Hz, 1H);3.78 (dd, J=11.5, 5.6 Hz, 1H); 3.34 (dd, J=11.4, 8.1 Hz, 1H); 3.13 (d,J=15.8 Hz, 1H); 2.74-2.76 (m, 1H); 2.59-2.60 (m, 1H); 2.41 (d, J=15.5Hz, 1H); 2.24-2.25 (m, 2H); 2.04 (s, 1H).

Intermediate 1.(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde

A solution of oxalyl chloride (7.35 g, 58.8 mmol) in dry dichloromethane(160 mL) was cooled to −60° C. under nitrogen and treated dropwise withdry dimethyl sulfoxide (9.55 g, 122.5 mmol) such that the temperaturedid not rise above −50° C. The mixture was stirred at −55° C. for 15minutes. A solution of(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol(12.40 g, 24.5 mmol) in dry dichloromethane (140 mL) was added such thatthe temperature did not rise above −50° C. The mixture was stirred for 2hours allowing the temperature to rise to −15° C. Triethylamine (12.64g, 125 mmol) was added dropwise such that the temperature did not riseabove −5° C. and the resultant mixture was stirred until the temperaturereached 0° C. Water (100 mL) was added, the phases were separated, theaqueous phase was extracted with further dichloromethane (×2) and thecombined organic phases were dried over sodium sulfate. The solids wereremoved by filtration, the filtrate was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel eluting with a mixture of ethyl acetate and dichloromethane (1:1 byvolume) followed by ethyl acetate to afford(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde as a white foam (11.8 g). 1H NMR (400 MHz, CDCl₃): δ 9.48 (s,1H); 7.93 (d, J=8.2 Hz, 2H); 7.84 (d, J=8.3 Hz, 2H); 7.39-7.40 (m, 3H);7.15-7.16 (m, 2H); 6.52 (d, J=2.4 Hz, 1H); 4.32 (dd, J=12.2, 2.1 Hz,1H); 3.90 (dd, J=11.0, 5.6 Hz, 1H); 3.14 (d, J=16.4 Hz, 1H); 2.71-2.73(m, 1H); 2.60 (d, J=16.4 Hz, 1H); 2.49-2.51 (m, 3H).

Intermediate 3.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol

2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesiumchloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at roomtemperature. The mixture was stirred for 10 minutes then warmed to 30°C. and stirred for 105 minutes. The mixture was cooled to −10° C. and asolution of(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(5.5 g, 10 mmol) in tetrahydrofuran (9 mL) was added dropwise. Thereaction mixture was stirred for 15 minutes at −10° C. followed bystirring at room temperature for 1 hour. The reaction mixture was cooledand treated with water (20 mL) followed by aqueous hydrochloric acid(1.0 M, 40 mL). The mixture was stirred for 10 minutes then extractedwith dichloromethane (×2) and the combined organic phases dried oversodium sulfate. The solids were removed by filtration, the filtrate wasconcentrated under reduced pressure and the residue purified by columnchromatography on silica gel (gradient: 20-80% ethyl acetate incyclohexane) to afford the diastereoisomeric (2:1) mixture(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanolas an off-white foam (3.25 g). 1H NMR (400 MHz, CDCl₃): δ 8.29 (d, J=4.8Hz, 1H); 8.00 (d, J=8.2 Hz, 2H); 7.84-7.86 (m, 3H); 7.44-7.46 (m, 1H);7.29-7.30 (m, 1.5H); 7.09-7.10 (m, 3.5H); 6.95-6.97 (m, 2.5 H); 6.41 (s,0.5H); 6.18 (s, 1H); 5.11 (s, 0.5H); 5.04 (s, 1H); 4.87 (s, 1H); 4.50(d, J=11.8 Hz, 1H); 4.10 (d, J=13.3 Hz, 2.5H); 3.80 (d, J=12.1 Hz,0.5H); 3.69 (s, 0.5H); 3.24 (d, J=16.6 Hz, 1H); 3.09-3.13 (m, 1.5H);2.54-2.58 (m, 2.5H); 2.25-2.27 (m, 1H); 2.11 (d, J=16.6 Hz, 1H); 1.43(s, 0.5H).

The following intermediate 4 was similarly prepared from the appropriatestarting materials:

Intermediate 4.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)-(R/S)-methanol

LCMS (Method C, ESI): RT 2.84 min, m+H=585.1; 1H NMR (400 MHz, CDCl₃): δ8.33 (d, J=2.2 Hz, 1H); 8.18 (dd, J=4.8, 1.7 Hz, 1H); 7.97 (d, J=8.2 Hz,2H); 7.85 (d, J=8.2 Hz, 2H); 7.69 (d, J=8.0 Hz, 1H); 7.04-7.05 (m, 4H);6.92 (dd, J=7.9, 4.8 Hz, 1H); 6.10 (d, J=2.3 Hz, 1H); 5.18 (s, 1H); 4.34(dd, J=12.3, 2.3 Hz, 1H); 4.15 (d, J=11.2 Hz, 1H); 3.42 (d, J=16.8 Hz,1H); 3.25 (s, 1H); 2.66 (t, J=12.0 Hz, 1H); 2.52 (d, J=15.4 Hz, 1H);2.34 (d, J=12.3 Hz, 1H); 2.17 (d, J=16.8 Hz, 1H).

Intermediate 5.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanol

2-Bromo-1-methyl-1H-imidazole (47 μL, 0.48 mmol) was dissolved indiethyl ether (2 mL) and cooled to −75° C. under argon. Butyl lithium(2.5 M in hexanes; 192 μL, 0.48 mmol) was added dropwise and the mixturestirred at −75° C. for 1 hour. A solution of(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(252 mg, 0.5 mmol) in diethyl ether (2 mL) was added dropwise. Thereaction mixture was stirred for 16 hours whilst warming slowly to roomtemperature. The reaction mixture was cooled and treated with water (10mL) and the phases separated. The organic phase was extracted withfurther diethyl ether (×2) followed by dichloromethane (×2). Thecombined organic phases were dried over sodium sulfate, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (gradient: 17.5 to 25% acetone in cyclohexane) to afford(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)-(R/S)-methanolas a white powder (82 mg) LCMS (Method A, ESI): RT 2.74 min, m+H=588.1

The following intermediates 6-9 were similarly prepared from theappropriate starting material:

Intermediate 6.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)-(R/S)-methanol

LCMS (Method C, ESI): RT 3.83 min, m+H=591.0; 1H NMR (400 MHz, CDCl₃): δ7.95 (t, J=9.5 Hz, 4H); 7.83 (t, J=8.6 Hz, 4H); 7.71 (d, J=3.2 Hz, 1H);7.39-7.40 (m, 2H); 7.35 (s, 1H); 7.30 (d, J=3.2 Hz, 1H); 7.21-7.22 (m,2H); 7.13-7.15 (m, 4H); 7.03-7.04 (m, 2H); 6.43 (s, 1H); 6.28 (d, J=2.3Hz, 1H); 5.47 (d, J=5.5 Hz, 1H); 5.27 (d, J=5.4 Hz, 1H); 4.34 (d, J=12.2Hz, 1H); 4.13 (t, J=8.8 Hz, 0.5H); 3.85 (d, J=5.6 Hz, 1H); 3.60-3.65 (m,1H); 3.40 (s, 0.5H); 3.37 (d, J=6.1 Hz, 1H); 3.15 (d, J=16.3 Hz, 1H);2.74 (d, J=12.3 Hz, 1H); 2.67 (dd, J=11.7, 3.8 Hz, 1H); 2.59 (d, J=16.7Hz, 1H); 2.38 (d, J=11.8 Hz, 1H); 2.19 (d, J=16.8 Hz, 1H); 1.43 (s, 3H).

Intermediate 7.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)-(R/S)-methanol

LCMS (Method A, ESI): RT 3.77 min, m+H=575.2.

Intermediate 8.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)-(R/S)-methanol

LCMS (Method A, ESI): RT 4.04 min, m+H=574.1.

Intermediate 9.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiophen-2-yl)-(R/S)-methanol

LCMS (Method A, ESI): RT 4.11 min, m+H=590.1.

Intermediate 10. (R)-tert-butyl1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

A solution of 2-bromopyridine (182 μL, 1.82 mmol) in dry diethyl ether(10 mL) was cooled to −78° C. and butyl lithium (2.5 M in hexanes, 730μL, 1.82 mmol) added dropwise. The mixture was stirred for 1 hour at−78° C. A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(800 mg, 2 mmol) in dry diethyl ether (10 mL) was added dropwise and thereaction mixture was stirred for 1 hour at −78° C. The reaction mixturewas stirred and warmed to 0° C. over 1 hour following which the reactionwas quenched by the addition of water (10 mL). The resultant mixture wasstirred for 30 minutes then extracted with dichloromethane (×2) and thecombined organic phases were dried over sodium sulfate. The solids wereremoved by filtration, the filtrate was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel (gradient: 30-50% ethyl acetate in cyclohexane) to afford thediastereoisomeric mixture (R)-tert-butyl1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas a straw-coloured foam (410 mg). LCMS (Method C, ESI): RT 2.64/2.81min, m+H=477.3.

Intermediate 11. (R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(410 mg, 0.86 mmol) in dry dichloromethane (10 mL) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (547 mg, 1.29mmol; Dess-Martin periodinane) and the reaction mixture was stirred for1 hour at room temperature. The reaction mixture was cooled and treatedwith saturated sodium hydrogen carbonate solution (20 mL) followed bydichloromethane (10 mL). The mixture was stirred for 10 minutes and thephases were separated. The aqueous phase was extracted with furtherdichloromethane (×2) and the combined organic phases dried over sodiumsulfate. The solids were removed by filtration, the filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (gradient: 20-40% ethyl acetate incyclohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas a pale yellow foam (185 mg). LCMS (Method B, ESI): RT 4.13 min,m+H=475.5; 1H NMR (400 MHz, CDCl₃): δ 8.68 (d, J=4.8 Hz, 2H); 7.44-7.45(m, 5H); 7.15-7.16 (m, 3H); 6.51 (s, 2H); 2.83 (br s, 5H); 2.49 (s, 1H);1.43 (s, 9H).

Alternative procedure: 2-Bromopyridine (110.0 g, 690 mmole) as asolution in diethyl ether (200 mL) was added to a cooled (−65° C.)solution of 2.5 M n-BuLi (275 mL, 690 mmol) in diethyl ether (200 mL).The mixture was stirred for 1 h at −70° C. to −65° C. To this solutionwas then added a suspension of (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(100.0 g, 230 mmol) in diethyl ether (1.0 L), keeping the temperaturebelow −65° C. The resulting solution was stirred for 2 hours at −70° C.to −65° C. The reaction mixture was quenched with glacial acetic acid(50 mL) and diluted with water (200 mL). The organic layer was washedwith 20% aqueous sodium chloride solution (250 mL), dried over magnesiumsulphate and concentrated to give a yellow foam. The crude product waspurified over silica gel (350 g, 240-400 mesh) by elution withheptane/ethyl acetate (8:1 to 2:1) to give (R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(109.5 g) as a yellow foam.

Intermediate 12.(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

(R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(180 mg, 0.39 mmol) was dissolved in HCl-dioxan (4 M, 4 mL) and theresultant solution was stirred vigorously at room temperature for 1.5hours. The reaction mixture was evaporated to afford(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a yellow solid. LCMS (Method B, ESI): RT 0.30 and 2.01 min,m+H=375.2.

Intermediate 13.(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanonein dichloromethane (2.5 mL) (2.7 mL, ˜0.2 mmol) containingdiisopropylamine (174 μL, 1 mmol) was added to6-chloro-pyridine-3-sulfonyl chloride (53 mg, 0.25 mmol) anddiisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 16hours. The reaction mixture was concentrated and the residue waspurified by column chromatography on silica gel (gradient: 20-30% ethylacetate in cyclohexane) to afford(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a white solid (85 mg). LCMS (Method B ESI): RT 3.92 min, m+H=550.0;1H NMR (400 MHz, CDCl₃): δ 8.66 (d, J=2.5 Hz, 1H); 8.61 (d, J=4.7 Hz,1H); 7.85-7.86 (m, 3H); 7.48-7.49 (m, 1H); 7.42-7.43 (m, 2H); 7.35 (d,J=8.4 Hz, 1H); 7.27 (s, 1H); 7.15-7.16 (m, 2H); 6.50 (s, 1H); 5.57 (d,J=12.4 Hz, 1H); 4.23 (d, J=16.9 Hz, 1H); 3.85-3.95 (m, 1H); 2.86-2.87(m, 3H); 2.66 (d, J=11.9 Hz, 1H); 2.53 (d, J=15.1 Hz, 1H).

The following intermediate 14 was similarly prepared from theappropriate starting materials:

Intermediate 14.(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.46 min, m+H=555.8; 1H NMR (400 MHz,CDCl₃): δ 8.68 (1H, dd, J=2.6, 0.7 Hz), 8.00 (1H, d, J=3.0 Hz), 7.89(1H, dd, J=8.3, 2.6 Hz), 7.69 (1H, d, J=3.0 Hz), 7.46-7.40 (2H, m), 7.37(1H, dd, J=8.3, 0.7 Hz), 7.29 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, d,J=2.2 Hz), 5.50 (1H, dd, J=12.5, 2.0 Hz), 4.17 (1H, d, J=16.7 Hz),3.97-3.91 (1H, m), 2.92-2.83 (3H, m), 2.69-2.63 (1H, m), 2.60-2.54 (1H,m).

Intermediate 15.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)-(R/S)-methanol

2-Methyl-[1,3,4]-oxadiazole (140 mg, 1.67 mmol) in dry tetrahydrofuran(5 mL) was cooled to −78° C. and butyl lithium (2.5 M solution inhexanes, 600 μL, 1.5 mmol) was added dropwise. The resultant reactionmixture was stirred for 10 minutes at −78° C. Magnesium bromide diethyletherate (400 mg, 1.55 mmol) was added in one portion and the mixturewas warmed to −45° C. over 1.5 hours where the temperature wasmaintained for 20 minutes. The reaction was re-cooled to −78° C. and asolution of(R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(100 mg, 0.4 mmol) in dry tetrahydrofuran (5 mL) was added dropwise andthe reaction mixture was stirred whilst allowing the reaction mixture towarm to −5° C. slowly. The reaction mixture was treated with saturatedammonium chloride solution (6 mL) and sufficient water to dissolveprecipitated salts. The mixture was extracted with dichloromethane (3×10mL) and the combined organic phases were dried over sodium sulfate. Thesolids were removed by filtration, the filtrate was concentrated underreduced pressure and the residue was purified by column chromatographyon silica gel (gradient: 50-100% ethyl acetate in cyclohexane) toafford, as a (˜2:1) mixture of diastereoisomers,(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)-(R/S)-methanolas an off-white foam (50 mg). LCMS (Method A, ESI): RT 3.38 min,m+H=590.4; 1H NMR (400 MHz, CDCl₃): δ 8.33 (s, 0.5H); 7.96 (d, J=8.2 Hz,2H); 7.85-7.87 (m, 3H); 7.42-7.43 (m, 1H); 7.30 (s, 1H); 7.20-7.21 (m,2H); 7.12-7.13 (m, 2.5H); 6.43 (s, 0.4H); 6.18 (d, J=2.3 Hz, 1H); 5.43(d, J=4.4 Hz, 1H); 4.99 (s, 0.4H); 4.30-4.32 (m, 1H); 3.68-3.75 (m, 1H);3.48 (d, J=16.7 Hz, 1H); 3.29 (d, J=16.2 Hz, 0.4H); 3.02-3.05 (m, 1H);2.57 (d, J=12.0 Hz, 3H); 2.43-2.48 (m, 2H); 2.35-2.37 (m, 2H); 2.20 (s,2H).

Intermediate 16.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol

To a solution of oxazole (99 μL, 0.5 mmol) in dry tetrahydrofuran (2.5mL) was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran,1.65 mmol, 1.65 mL) and the mixture was stirred at room temperature for1 hour. The mixture was cooled to −78° C. and butyl lithium (1.6 Msolution in hexanes, 1.20 mL, 1.95 mmol) was added dropwise. Thereaction mixture was stirred for 40 minutes at −78° C. A solution of(R)-1-(4-fluorophenyl)-6((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(250 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added dropwise andthe reaction mixture was stirred at −78° C. for 2 hours. The reactionmixture was warmed to room temperature and stirred for 2 hours. Thereaction mixture was poured into ethanol/acetic acid mixture (95:5, v/v;50 mL) and stirred at room temperature for 18 hours. The solvent wasevaporated and the residue was dissolved in ethyl acetate (30 mL). Theorganic phase was washed with water (20 mL), saturated sodiumbicarbonate (2×20 mL) and brine (20 mL). The organic phase was driedover sodium sulfate, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (gradient: 0-4% methanolin dichloromethane) to afford, as a mixture of diastereoisomers,(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanolas a white foam (136 mg). LCMS (Method A, ESI): RT 3.68 min, m+H=575.0.

The following intermediates 17-20 were similarly prepared from theappropriate starting material:

Intermediate 17.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol

LCMS (Method F, ES-API): RT 2.26 min, m+H=521.1.

Intermediate 18.(R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)-(R/S)-methanol

LCMS (Method F, ES-API): RT 1.70, 1.76 min, m+H=583.2.

Intermediate 19.(R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)-(R/S)-methanol

LCMS (Method F, ES-API): RT 1.97/2.10 min (mixture of diastereomers),m+H=599.2.

Intermediate 20.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)-(R/S)-methanol

LCMS (Method F, ES-API): RT 1.90 min, m+H=601.2.

Intermediate 21. (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

2-Bromothiazole (0.643 mL, 7.14 mmol) in dry ether (7 mL) was added ton-butyllithium (2.5 M in Hexanes) (2.92 mL, 7.31 mmol) in dry ether (5mL) at −78° C. The reaction mixture was stirred at −78° C. for 45minutes. A solution of (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(1.0 g, 2.339 mmol) in dry ether (15 mL) was added dropwise and thereaction mixture was stirred for 0.5 hour at −78° C. Water (60 mL) wasadded and the reaction mixture was stirred at room temperature for 10minutes. The aqueous layer was extracted with dichloromethane (3×75 mL).The combined organic extracts were washed with brine (100 mL), driedover magnesium sulfate, filtered and concentrated in vacuo to give adark orange oil. The crude product was purified by column chromatographyon silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford(R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas an off-white solid (984 mg). LCMS (Method F, ES-API): RT 2.64 min,m+H=480.9; 1H NMR (400 MHz, CDCl₃): δ 8.06 (1H, d, J=3.0 Hz), 7.64 (1H,s), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, s),5.60 (1H, br s), 4.49 (1H, d, J=15.0 Hz), 4.21 (1H, br s), 3.28-3.25(1H, m), 2.86-2.81 (3H, m), 2.49 (1H, d, J=14.5 Hz), 1.55 (9H, s).

The following intermediates 22-30 were similarly prepared starting fromthe appropriate starting material:

Intermediate 22. (R)-tert-butyl1-(4-fluorophenyl)-4a-(1-methyl-1H-1,2,4-triazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.51 min, m+H=479.3.

Intermediate 23 (R)-tert-butyl1-(4-fluorophenyl)-4a-(pyrazine-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.48 min, m+H=476.3.

Intermediate 24. (R)-tert-butyl1-(4-fluorophenyl)-4a-(5-methoxypicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.67 min, m+H=505.2.

Intermediate 25. (R)-tert-butyl1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.82 min, m+H=489.3.

Intermediate 26. (R)-tert-butyl4a-(4-ethylpicolinoyl)-1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 3.05 min, m+H=503.3.

Intermediate 27. (R)-tert-butyl1-phenyl-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.65 min, m+H=457.

Intermediate 28. (R)-tert-butyl1-(4-fluorophenyl)-4a-(2-(pyrrolidin-1-yl)isonicotinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.06 min, m+H=544.0.

Intermediate 29. (R)-tert-butyl1-(4-chlorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 3.02 min, m+H=559.2.

Intermediate 30. (R)-tert-butyl4a-picolinoyl-1-(4-(trifluoromethyl)phenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.90 min, m+H=525.

Intermediate 31.(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone2,2,2-trifluoroacetate

A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(1.0 g, 1.561 mmol) in 20% trifluoroacetic acid/dichloromethane (100 mL)was stirred at room temperature for 30 minutes. The solvent was removedin vacuo then the crude residue azeotroped twice with toluene to give(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanonetrifluoroacetate as an orange solid (0.584 g). LCMS (Method F, ES-API):RT 1.30 min, m+H=381.0; 1H NMR (400 MHz, CDCl₃): δ 8.02 (1H, d, J=2.7Hz), 7.78 (1H, d, J=2.7 Hz), 7.48 (1H, s), 7.46-7.41 (2H, m), 7.24-7.16(2H, m), 6.57 (1H, s), 4.45 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=16.2 Hz),3.74-3.65 (2H, m), 3.34 (1H, d, J=13.2 Hz), 3.12 (1H, br t, J=10.6 Hz),2.89 (1H, d, J=16.2 Hz), 2.82 (1H, d, J=13.1 Hz), 2.62 (1H, d, J=15.4Hz).

Intermediate 32. (R)-tert-butyl1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

A solution of 4-bromo-2-(trimethylsilyl)thiazole (304 μL, 1.784 mmol) indry ether (2 mL) was added to a solution of butyllithium (2.5 M inHexanes) (731 μL, 1.828 mmol) in dry ether (1 mL) at −78° C. Thereaction mixture was stirred at −78° C. for 30 minutes. A solution of(R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(250 mg, 0.585 mmol) in dry ether (5 mL) was added dropwise and thereaction mixture was stirred for 0.5 hour at −78° C. then slowly warmedto −50° C. over 2 hours. Water (10 mL) was added and the reactionmixture was stirred at room temperature for 10 minutes. The aqueouslayer was extracted with ethyl acetate (3×15 mL). The combined organicextracts were washed with brine (20 mL), dried over magnesium sulfate,filtered and concentrated in vacuo to give a dark orange oil. The crudeproduct was purified by column chromatography on silica gel (gradient:0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas a pale yellow foamy solid (76 mg). LCMS (Method F, ES-API): RT 2.65min, m+H=553.3.

Intermediate 33. (R)-methyl1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

A solution of (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(2.0 g, 4.68 mmol) in 20% trifluoroacetic acid/dichloromethane (50 mL)was stirred at room temperature for 1 hour. The solvent was removed invacuo, azeotroping three times with toluene (˜20 mL), to give a darkorange oil. The oil was dissolved in dichloromethane (50 mL) and3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.900 ml, 5.61 mmol) wasadded followed by diisopropylethylamine (4.09 ml, 23.39 mmol). Thereaction mixture was stirred at room temperature for 20 minutes, andthen solvent removed in vacuo to give a dark orange oil. The crudeproduct was purified by chromatography on silica gel (gradient: 0-45%ethyl acetate in isohexane) to afford (R)-methyl1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(931 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.62 min,m+H=536.2.

The following intermediates 34-54 were similarly prepared from theappropriate starting material:

Intermediate 34. (R)-methyl1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.52 min, m+H=482.2.

Intermediate 35. (R)-methyl1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.44 min, m+H=498.

Intermediate 36. (R)-methyl6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.57 min, m+H=500.

Intermediate 37. (R)-methyl1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.40 min, m+H=468.2.

Intermediate 38. (R)-methyl6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.58 min, m+H=502.2.

Intermediate 39. (R)-methyl1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS (Method F, ES-API): RT 2.51 min, m+H=482.

Intermediate 40. (R)-methyl6((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.66 min, m+H=554.

Intermediate 41. (R)-methyl1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.59 min, m+H=522.1.

Intermediate 42. (R)-methyl64(3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.88 min, m+H=554.2.

Intermediate 43. (R)-methyl6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.38 min, m+H=486.2.

Intermediate 44. (R)-methyl6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.71 min, m+H=536.

Intermediate 45. (R)-methyl1-(pyridin-3-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.24 min, m+H=519.

Intermediate 46. (R)-methyl6-((3,4-dichlorophenyl)sulfonyl)-1-phenyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.68 min, m+H=519.

Intermediate 47. (R)-methyl6-(3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.48 min, m+H=504.

Intermediate 48. (R)-methyl6-((3,4-dichlorophenyl)sulfonyl)-1-(3,4-difluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.78 min, m+H=555.

Intermediate 49. (R)-methyl6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.59 min, m+H=520.0.

Intermediate 50. (R)-methyl1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.00 min, m+H=472.0.

Intermediate 51. (R)-methyl1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 1.99 min, m+H=472.

Intermediate 52. (R)-methyl6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.23 min, m+H=486.2.

Intermediate 53. (R)-methyl1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.15 min, m+H=472.2.

Intermediate 54. (R)-methyl6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.26 min, m+H=486.1.

Intermediate 55. (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

2-(Trimethylsilyl)thiazole (285 μl, 1.784 mmol) in dry ether (2 mL) wasadded to butyllithium (2.5 M in Hexanes) (731 μl, 1.828 mmol) in dryether (1 mL) at −78° C. The reaction mixture was stirred at −78° C. for30 minutes. A solution of (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(250 mg, 0.585 mmol) in dry ether (6 mL) was added dropwise and thereaction mixture was stirred for 0.5 hour at −78° C. Water (10 mL) wasadded and the reaction mixture was stirred at room temperature for 10minutes. The aqueous layer was extracted with ethyl acetate (3×15 mL).The combined organic extracts were washed with brine (20 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to give an orangesolid. The crude product was purified by chromatography on silica gel(gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-5-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(88 mg) as a yellow solid. LCMS (Method F, ES-API): RT 2.38 min,m+H=481.2.

Intermediate 56.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol

Superhydride (1M solution in tetrahydrofuran, 43.2 ml, 43.2 mmol) wasadded slowly to a solution of (R)-methyl1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(5.2 g, 10.80 mmol) in tetrahydrofuran (100 mL) at 0° C. and stirred for2 hours. The reaction was quenched with ammonium chloride solution(aqueous, 100 mL) and ethyl acetate (100 mL) was added. The phases wereseparated and the organic phase was washed with brine (100 mL), dried(sodium sulphate) and solvent removed to give a yellow oil. The crudeproduct was purified by chromatography on silica gel (gradient: 0-80%ethyl acetate in isohexane) to afford(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol(4.45 g) as a white solid. LCMS (Method F, ES-API): RT 2.36 min,m+H=454.

The following intermediate 57 was similarly prepared from theappropriate starting materials:

Intermediate 57.(R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol

LCMS (Method F, ES-API): RT 2.40 min, m+H=476.2.

Intermediate 58.(R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde

(R)-(1-(4-Fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol(3.5 g, 7.72 mmol) was dissolved in dichloromethane (80 mL) andDess-Martin Periodinane (5.24 g, 12.35 mmol) was added. The reaction wasstirred at room temperature for 1 hour. A saturated solution of sodiumhydrogen carbonate (aqueous, 50 ml) was added and the mixture wasstirred for 10 minutes. The phases were separated and solvent removed togive a pale yellow solid. The crude product was purified bychromatography on silica gel (gradient: 0-80% ethyl acetate inisohexane) to afford (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(2.9 g) as a very pale yellow solid. LCMS (Method F, ES-API): RT 2.46min, m+H=452.

The following intermediates 59-61 were similarly prepared from theappropriate starting material:

Intermediate 59.(R)-6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde

LCMS (Method F, ES-API): RT 2.54 min, m+H=474.2.

Intermediate 60.(R)-1-(4-fluorophenyl)-6-(3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde

LCMS (Method F, ES-API): RT 2.85 min, m+H+CH₃OH (sample prepared inCH₃OH, giving methanol hemiacetal)=524.2.

Intermediate 61. (R)-tert-butyl1-(4-fluorophenyl)-4a-(1-methyl-1H-pyrazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS (Method F, ES-API): RT 2.24 min, m+H=478.2.

Intermediate 62.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)-(R/S)-methanol

To a stirred solution of 2-(tributylstannyl)pyrimidine (428 μl, 1.351mmol) in dry tetrahydrofuran (5 mL) was added butyllithium (2.5 M inhexanes) (554 μl, 1.384 mmol) at −78° C. The reaction mixture wasstirred at −78° C. for 1.5 hours. A solution of(R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde(200 mg, 0.443 mmol) in dry tetrahydrofuran (5 mL) was added dropwiseand the reaction mixture was stirred for 1.5 hours at −78° C. Water (25mL) was added and the aqueous layer was extracted with ethyl acetate(2×30 mL). The combined organic layers were washed with brine (30 mL),dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was partitioned between acetonitrile (25 mL) and hexanes (15mL). The hexane layer was discarded. The acetonitrile layer wasconcentrated in vacuo to give a pale orange oil. The crude product waspurified by chromatography on silica gel (gradient: 0-100% ethyl acetatein isohexane) to afford(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanol(75 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.27 min,m+H=532.2.

Intermediate 63. 2-(benzylthio)-6-(trifluoromethyl)pyridine

To a suspension of sodium hydride (0.170 g, 4.24 mmol) intetrahydrofuran (10 mL) was added phenylmethanethiol (0.338 ml, 2.88mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15minutes then 2-fluoro-6-(trifluoromethyl)pyridine (0.365 ml, 3.03 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 30minutes. Methanol (1 mL) was added carefully and the reaction mixturewas stirred at 0° C. for a further 10 minutes then water (5 mL) anddichloromethane (10 mL) were added. The organic layer was recoveredusing a phase separator cartridge then concentrated in vacuo to give2-(benzylthio)-6-(trifluoromethyl)pyridine (538 mg) as a colourless oil.LCMS (Method F, ES-API): RT 2.80 min, m+H=270.1.

Intermediate 64. 6-(trifluoromethyl)pyridine-2-sulfonyl chloride

To a suspension of 2-(benzylthio)-6-(trifluoromethyl)pyridine (580 mg,2.154 mmol) in acetic acid (8 mL) and water (4 mL) was addedN-chlorosuccinamide (1438 mg, 10.77 mmol), and the mixture was stirredat room temperature for 1 hour. Water (10 mL) was added and the mixturewas extracted with dichloromethane (2×10 mL). The organic extract waswashed with saturated aqueous sodium hydrogen carbonate solution (10 mL)and saturated brine (10 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to give 6-(trifluoromethyl)pyridine-2-sulfonylchloride (436 mg) as a colourless oil. LCMS (quenching with morpholine;Method F, ES-API): RT 1.84 min, (m+H+morpholine-Cl)=297.1.

The following intermediates 65-66 were similarly prepared fromappropriate starting materials:

Intermediate 65. 2-(trifluoromethyl)pyridine-4-sulfonyl chloride

LCMS (quenching with morpholine; Method F, ES-API): RT 2.03 min,(m+H+morpholine-Cl)=297.1.

Intermediate 66. 4-(trifluoromethyl)pyridine-2-sulfonyl chloride

LCMS (quenching with morpholine; Method F, ES-API): RT 1.85 min,(m+H+morpholine-Cl)=297.1.

Intermediate 67. 3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride

3-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmol) was dissolved inacetonitrile (10 mL). The solution was cooled to 0° C., and treated withtetrafluoroboric acid (48% aqueous solution, 6.49 ml, 41.9 mmol) andtert-butyl nitrite (4.98 ml, 41.9 mmol). The reaction mixture wasmaintained at 0° C. for 1 hour. In the meantime, a suspension of copper(I) chloride (4.15 g, 41.9 mmol) in acetonitrile (40 mL) at 0° C. wassaturated with sulfur dioxide gas by bubbling the gas through thesuspension with vigorous stirring for 30 minutes. When the diazotizationreaction was complete after 1 hour, this solution was added dropwise tothe suspension of copper (I) chloride, causing vigorous evolution ofgas. The reaction mixture was then allowed to warm to room temperatureand stirred for 1 hour, after which time it was poured onto 100 mL of anice/water slurry. Diethyl ether (150 mL) was added, causing aprecipitate to form, which was removed by filtration. The filtrate waswashed with water (100 mL) and brine (100 mL), dried over magnesiumsulfate, filtered, and concentrated in vacuo to give3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (6.62 g) as anorange oil. LCMS (quenching with morpholine; Method F, ES-API): RT 2.25min, (m+H+morpholine-Cl)=314.1.

Intermediate 68. (R,Z)-2-tert-butyl 8a-methyl7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate

Lithium hexamethyldisilazide (12.93 ml, 12.93 mmol) was added to diethylether (20 mL) at −78° C. (R)-2-tert-butyl 8a-methyl6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate(WO2005087769) (1.0 g, 3.23 mmol) in ether (5 mL) was added followed bythe addition of 2,2,2-trifluoroethyl formate (2.51 ml, 25.9 mmol) after20 minutes. The reaction was stirred at −78° C. for 2 hours then allowedto slowly warm to room temperature. 1M hydrochloric acid (8 mL) wasadded, followed by water (10 mL) and ethyl acetate (10 mL). The organicphase was separated, washed with brine, dried (magnesium sulfate) andsolvent removed to give (R,Z)-2-tert-butyl 8a-methyl7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate(1.09 g) as a yellow oil. LCMS (Method F, ES-API): RT 1.99 min, m-H=336.

Intermediate 69. (R)-6-tert-butyl 4a-methyl1-phenyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate

(R,Z)-2-tert-butyl 8a-methyl7-(hydroxymethylene)-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2,8a(1H)-dicarboxylate(1.09 g, 3.23 mmol) was suspended in acetic acid (20 mL), and sodiumacetate trihydrate (0.265 g, 3.23 mmol) and phenylhydrazine (0.318 ml,3.23 mmol) were added. The reaction mixture was stirred at roomtemperature for 30 minutes, then water (20 mL) and dichloromethane (20mL) were added and the phases were separated via a phase separator. Thesolvent was removed to give an orange oil. The crude product waspurified by chromatography on silica gel (gradient: 0-50% ethyl acetatein isohexane) to afford (R)-6-tert-butyl 4a-methyl1-phenyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(694 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.48 min,m+H=410.

The following intermediates 70-73 were similarly prepared fromappropriate starting materials:

Intermediate 70. (R)-6-tert-butyl 4a-methyl1-(pyridin-3-yl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate

LCMS (Method F, ES-API): RT 2.03 min, m+H=411

Intermediate 71. (R)-6-tert-butyl 4a-methyl1-(3,4-difluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate

LCMS (Method F, ES-API): RT 2.58 min, m+H=446.

Intermediate 72. (R)-6-tert-butyl 4a-methyl1-(4-chlorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate

LCMS (Method F, ES-API): RT 2.65 min, m+H=444.2.

Intermediate 73. (R)-6-tert-butyl 4a-methyl1-(4-(trifluoromethyl)phenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate

LCMS (Method F, ES-API): RT 2.76 min, m+H=478.

Intermediate 74. 4-(benzylthio)-2-(trifluoromethyl)pyridine

4-Chloro-2-(trifluoromethyl)pyridine (141 μl, 1.102 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (199 μl, 1.322 mmol), andphenylmethanethiol (129 μl, 1.102 mmol) were dissolved in drydimethylformamide (2 mL). The reaction mixture was heated at 100° C. ina microwave for 30 minutes, then partitioned between ether (25 mL) andwater (25 mL). The aqueous layer was extracted with ether (2×25 mL) andthe combined organic layers were dried over magnesium sulfate, filteredand concentrated in vacuo to give a pale yellow oil. The crude productwas purified by chromatography on silica gel (gradient: 0-30% ethylacetate in isohexane) to afford4-(benzylthio)-2-(trifluoromethyl)pyridine (224 mg) as a colourless oil.LCMS (Method F, ES-API): RT 2.79 min, m+H=270.1.

Intermediate 75.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol

To a solution of (R)-methyl1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(1.0 g, 1.918 mmol) in anhydrous dichloromethane (30 mL) at −78° C.under a nitrogen atmosphere was added diisobutyl aluminium hydride(DIBAL-H) (1 M in Heptane) (7.67 ml, 7.67 mmol) dropwise over 10minutes. The reaction mixture was stirred at −78° C. for 1 hour. Water(10 mL) was then added and the reaction mixture stirred at −78° C. for 5minutes, then warmed to room temperature over 15 minutes. The solutionwas partitioned between ethyl acetate (150 mL) and Rochelle's salt (150mL). The organic layer was washed with Rochelle's salt (150 mL), brine(100 mL), dried over magnesium sulfate, filtered and concentrated invacuo to give an off white solid. The crude product was purified bychromatography on silica gel (gradient: 0-90% ethyl acetate inisohexane) to afford(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanol(680 mg) as a white solid. LCMS (Method F, ES-API): RT 2.58 min,m+H=494.2.

Intermediate 76. 2-(benzylthio)-4-(trifluoromethyl)pyridine

To a solution of phenylmethanethiol (356 μl, 3.03 mmol) and2-fluoro-4-(trifluoromethyl)pyridine (369 μl, 3.03 mmol) indimethylformamide (5 mL) was added potassium carbonate (628 mg, 4.54mmol). The reaction mixture was stirred at 60° C. for 2 hours, thencooled to room temperature, water (10 mL) was added, and the mixture wasextracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with saturated aqueous sodium hydrogen carbonate solution (20mL), brine (20 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to give a pale yellow oil. The crude product waspurified by chromatography on silica gel (gradient: 0-20% ethyl acetatein isohexane) to afford 2-(benzylthio)-4-(trifluoromethyl)pyridine (510mg) as a colourless oil. LCMS (Method F, ES-API): RT 3.04 min,m+H=270.1.

Intermediate 77. 4-bromo-2-(pyrrolidin-1-yl)pyridine

2,4-Dibromopyridine (1.0 g, 4.22 mmol) was dissolved in ethanol (40 mL)and pyrrolidine (1.733 ml, 21.11 mmol) was added. The reaction mixturewas stirred at 70° C. for 20 hours. The reaction mixture was cooled toroom temperature and the solvent was removed in vacuo to give a paleyellow solid. The crude product was purified by chromatography on silicagel (gradient: 0-80% ethyl acetate in isohexane) to afford2-bromo-4-(pyrrolidin-1-yl)pyridine (460 mg) as a white solid, and4-bromo-2-(pyrrolidin-1-yl)pyridine (260 mg) as a white solid. LCMS(Method F, ES-API): RT 0.79 min, m+H=227.1/229.1.

Intermediate 78.(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

(R)-tert-butyl1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(2 g, 2.65 mmol) was dissolved in a solution of HCl in dioxane (4M)(13.27 ml, 53.1 mmol) and the reaction mixture was stirred at roomtemperature for 45 minutes. The solvent was removed in vacuo to give anorange gum. This was treated with a mixture of 10% methanol (containing1% of ammonia)/dichloromethane until complete dissolution of the gum,then the solvent was removed in vacuo to give an orange solid. The crudeproduct was purified by chromatography on silica gel (gradient: 0-10%methanol (containing 1% of ammonia) in dichloromethane) to give(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone(810 mg) as a pale orange solid. LCMS (Method F, ES-API): RT 1.41 min,m+H=443.2.

Intermediate 79. 1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid,ammonium salt

Chlorosulphonic acid (2 ml, 30.1 mmol) was added cautiously dropwise bypipette over 5 minutes to stirred neat 1-methylpyridin-2(1H)-one (8.09ml, 82 mmol) and the resulting viscous solution was stirred at 50° C.for 40 hours. The cooled solidified reaction mixture was then addedcautiously to water (100 ml), giving a clear brown solution. Thissolution was concentrated in vacuo to 40 ml, then made basic withconcentrated ammonia solution, and washed with dichloromethane (6×100ml). The aqueous phase was then evaporated to give a brown slurry whichwas triturated in methanol and filtered. The filtrate was evaporated togive 1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid, ammonium salt(3 g) as a brown solid. LCMS (Method F, ES-API): RT 0.46 min, m-H=188.0.

Intermediate 80. (R)-methyl6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

To a solution of (R)-methyl1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(150 mg, 0.288 mmol) in dimethyl sulphoxide (4 mL) was added sodiummethoxide (25% in methanol) (65.8 μl, 0.288 mmol) dropwise. The reactionmixture was stirred at room temperature for 1 hour, then allowed tostand at room temperature overnight. The crude product was purified bycolumn chromatography on silica gel (gradient: 0-50% ethyl acetate inisohexane) to afford (R)-methyl64(3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazol[3,4-g]isoquinoline-4a-carboxylate (150 mg)as a pale yellow solid. LCMS (Method F, ES-API): RT 2.51 min, m+H=534.2.

Intermediate 81. (R)-tert-butyl1-(4-fluorophenyl)-4a-(R/S)-hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

To a solution of n-butyl lithium (2.5 M in Hexanes) (312 μl, 0.780 mmol)in tetrahydrofuran (2 mL) was added 4-iodo-1-methyl-1H-pyrazole (157 mg,0.755 mmol) in tetrahydrofuran (1 mL) at −78° C. The mixture was stirredat this temperature for 1 hour, then a solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(100 mg, 0.252 mmol) in tetrahydrofuran (1 mL) was added dropwise to thereaction mixture. The mixture was stirred at this temperature for 30minutes. Water (6 mL) and dichloromethane (8 mL) were added and thephases were separated using a phase separator cartridge. The solvent wasremoved in vacuo to give an orange oil.

A second reaction was performed with inverse addition of n-butyllithium. To a solution of 4-iodo-1-methyl-1H-pyrazole (157 mg, 0.755mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M inHexanes) (312 μl, 0.780 mmol) at −78° C. The mixture was stirred at thistemperature for 1 hour, then a solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(100 mg, 0.252 mmol) in tetrahydrofuran (1 mL) was added dropwise to thereaction mixture. The mixture was stirred at this temperature for 30minutes. Water (6 mL) and dichloromethane (8 mL) were added and thephases were separated using a phase separator cartridge. The solvent wasremoved in vacuo to give an orange oil, with a similar composition tothe previous reaction product according to LC/MS analysis.

Both reaction products were combined and purified by columnchromatography on silica gel (gradient: 0-100% ethyl acetate inisohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-(hydroxy(l-methyl-1H-pyrazol-4-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(41 mg) as a pale orange gum. LCMS (Method F, ES-API): RT 2.21 min,m+H=480.2.

Intermediate 82. ((R)-tert-butyl1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate))

A solution of 2-bromo-4-(trifluoromethyl)pyridine (2.344 ml, 18.95 mmol)in dry ether (15 mL) was added dropwise over 15 minutes to a solution ofisopropylmagnesium chloride (2M, 9.47 ml, 18.95 mmol) in dry ether (30mL) at 0° C., during which the solution darkened to a brown colour.After stirring at 0° C. for a further 45 minutes a solution of(R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(2.7 g, 6.32 mmol) in dry ether:tetrahydrofuran (4:1, 30 mL total) wasadded dropwise over 20 minutes at 0° C. The resulting dark colouredsolution was stirred at 0° C. for 20 minutes, then stirred at roomtemperature for a further 2 hours. The reaction mixture was diluted withice/water (20 mL), acidified with 1M HCl (40 mL) and extracted withethyl acetate (100 mL). The organic phase was washed sequentially withwater (50 mL), saturated sodium hydrogen carbonate solution (50 mL) andbrine (30 mL), dried (magnesium sulphate), filtered and evaporated invacuo to give a brown gum. This was dissolved in acetonitrile (50 mL),1M HCl (10 mL) was added, and the solution stirred for 2 hours at roomtemperature. Ethyl acetate (150 mL) was added and the organic phasewashed sequentially with brine (30 mL), saturated aqueous sodiumhydrogen carbonate (50 mL) and further brine (30 mL). The organic phasewas then dried (magnesium sulphate), filtered and evaporated in vacuo.

The residual brown gum was purified twice by column chromatography onsilica gel (gradients: 0-10% ethyl acetate in dichloromethane, and 0-30%ethyl acetate in isohexane) to give (R)-tert-butyl1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(2.65 g) as a light brown foam. LCMS (Method F, ES-API): RT 2.91 min,m+H=543.

Intermediate 83. ((R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate)

A suspension of isopropylmagnesium chloride (2M in tetrahydrofuran,1.755 ml, 3.51 mmol) in dry ether (4.5 mL) at 0° C. was treated dropwisewith a solution of 4-bromo-2-(trimethylsilyl)thiazole (0.829 g, 3.51mmol) in dry ether (2.5 mL) and the resulting suspension stirred at 0°C. for 1 hour. The suspension was then treated dropwise with a solutionof (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(0.5 g, 1.17 mmol) in dry ether:tetrahydrofuran (4:1, 5 mL total volume)and the resulting suspension stirred at 0° C. for 15 minutes. Thereaction mixture was then allowed to warm to room temperature, and thesolution stirred for a further 3 hours. The reaction mixture was cooledto 0° C., and ice water (50 mL) added dropwise. The aqueous layer wasextracted with ethyl acetate (3×50 mL) and the combined organic extractswashed with brine (50 mL) and dried over magnesium sulphate. The solventwas removed to give an orange oil. This was dissolved in acetonitrile(12 mL) and treated dropwise with 1M aqueous HCl (1171 μl, 1.171 mmol)and the resulting solution stirred at room temperature for 1.5 hours.The reaction was diluted with ethyl acetate (150 mL) and washedsequentially with brine (50 mL), saturated aqueous sodium hydrogencarbonate solution (50 mL), and further brine (50 mL). The organic layerwas dried over magnesium sulphate and the solvent removed. The crudeproduct was purified by column chromatography on silica gel (gradient:5-95% ethyl acetate in isohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(238 mg) as a pale yellow gum. LCMS (Method F, ES-API): RT 2.55 min,m+H=481.2.

Intermediate 84. 4-(benzylthio)-1H-1,2,3-triazole

Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution ofsodium 1H-1,2,3-triazole-5-thiolate (12.2 g, 99 mmol) in ethanol (100mL) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred for 20 minutes. The reaction mixture was dilutedwith ethyl acetate (100 mL) and washed with water (100 mL), brine (100mL) and dried (sodium sulphate). The solvent was removed to give4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid. LCMS (MethodF, ES-API): RT 1.66 min, m+H=191.9; 1H NMR (400 MHz, CDCl₃): δ 9.72 (1H,v br s), 7.47 (1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s).

Intermediates 85. Methylated Triazole

85a 4-(benzylthio)-2-methyl- 2H-1,2,3-triazole

85b 5-(benzylthio)-1-methyl- 1H-1,2,3-triazole

85c 4-(benzylthio)-1-methyl- 1H-1,2,3-triazole

Iodomethane (2.409 ml, 38.7 mmol) was added dropwise to a mixture of4-(benzylthio)-1H-1,2,3-triazole (3.7 g, 19.35 mmol) and potassiumcarbonate (5.88 g, 42.6 mmol) in N,N-dimethylformamide (40 mL) at 0° C.The reaction was then allowed to warm to room temperature and stirredfor 1 hour. Water (40 mL) and ethyl acetate (40 mL) were added and thephases separated. The organic phase was washed with water (2×40 mL),brine (40 mL), dried (sodium sulphate) and solvent was removed to give ayellow oil. The crude product was purified by column chromatography onsilica gel (gradient: 0-100% ethyl acetate in isohexane) to afford threefractions:

Fraction 1 (1.61 g) as a colourless oil. LCMS (Method F, ES-API): RT2.05 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.68 (1H, s), 7.35-7.19(5H, m), 4.18 (2H, s), 4.11 (3H, s).

Fraction 2 (816 mg) as a pale yellow oil. LCMS (Method F, ES-API): RT1.79 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (1H, s), 7.36-7.23(3H, m), 7.22-7.14 (2H, m), 4.09 (2H, s), 3.73 (3H, s).

Fraction 3 (883 mg) as a pale yellow oil. LCMS (Method F, ES-API): RT1.68 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 8.02 (1H, s), 7.34-7.19(5H, m), 4.12 (2H, s), 4.00 (3H, s).

The following intermediates 86-88 were similarly prepared fromappropriate starting materials:

Intermediates 86. Ethylated Triazole

86a 4-(benzylthio)-2-ethyl- 2H-1,2,3-triazole

86b 5-(benzylthio)-1-ethyl- 1H-1,2,3-triazole

86c 4-(benzylthio)-1-ethyl- 1H-1,2,3-triazole

Fraction 1: LCMS (Method F, ES-API): RT 2.24 min, m+H=220; 1H NMR (400MHz, DMSO-d6): δ 7.69 (1H, s), 7.32-7.21 (5H, m), 4.39 (2H, q, J=7.3Hz), 4.18 (2H, s), 1.40 (3H, t, J=7.3 Hz).

Fraction 2: LCMS (Method F, ES-API): RT 1.96 min, m+H=220; 1H NMR (400MHz, DMSO-d6): δ 7.74 (1H, s), 7.32-7.24 (3H, m), 7.21-7.16 (2H, m),4.13 (2H, q, J=7.3 Hz), 4.12 (2H, s), 1.23 (3H, t, J=7.3 Hz).

Fraction 3: LCMS (Method F, ES-API): RT 1.85 min, m+H=220; 1H NMR (400MHz, DMSO-d6): δ 8.07 (1H, s), 7.31-7.19 (5H, m), 4.33 (2H, q, J=7.3Hz), 4.11 (2H, s), 1.38 (3H, t, J=7.3 Hz).

Intermediates 87. Propylated Triazole

87a 4-(benzylthio)-2- propyl-2H-1,2,3- triazole

87b 5-(benzylthio)-1- propyl-1H-1,2,3- triazole

87c 4-(benzylthio)-1- propyl-1H-1,2,3- triazole

Fraction 1: LCMS (Method F, ES-API): RT 2.36 min, m+H=234.2; 1H NMR (400MHz, DMSO-d6): δ 7.69 (1H, s), 7.28-7.27 (4H, m), 7.25-7.20 (1H, m),4.32 (2H, t, J=7.0 Hz), 4.18 (2H, s), 1.83 (2H, sext, J=7.0 Hz), 0.78(3H, t, J=7.0 Hz).

Fraction 2: LCMS (Method F, ES-API): RT 2.08 min, m+H=234.2; 1H NMR (400MHz, DMSO-d6): δ 7.74 (1H, s), 7.38-7.12 (5H, m), 4.13 (2H, s), 4.06(2H, t, J=7.0 Hz), 1.66 (2H, sext, J=7.0 Hz), 0.74 (3H, t, J=7.0 Hz).

Fraction 3: LCMS (Method F, ES-API): RT 2.01 min, m+H=234.2; 1H NMR (400MHz, DMSO-d6): δ 8.04 (1H, s), 7.29-7.19 (5H, m), 4.26 (2H, t, J=7.0Hz), 4.10 (2H, s), 1.77 (2H, sext, J=7.0 Hz), 0.78 (3H, t, J=7.0 Hz).

Intermediates 88. Isopropylated Triazole

88a 4-(benzylthio)-2- isopropyl-2H-1,2,3- triazole

88b 5-(benzylthio)-1- isopropyl-1H-1,2,3- triazole

88c 4-(benzylthio)-1- isopropyl-1H-1,2,3- triazole

Fraction 1: LCMS (Method F, ES-API): RT 2.41 min, m+H=234; 1H NMR (400MHz, DMSO-d6): δ 7.67 (1H, s), 7.31-7.21 (5H, m), 4.76 (1H, sept, J=6.7Hz), 4.17 (2H, s), 1.44 (6H, d, J=6.7 Hz).

Fraction 2: LCMS (Method F, ES-API): RT 2.09 min, m+H=234; 1H NMR (400MHz, DMSO-d6): δ 7.77 (1H, s), 7.32-7.12 (5H, m), 4.60 (1H, sept, J=6.7Hz), 4.11 (2H, s), 1.29 (6H, d, J=6.7 Hz).

Fraction 3: LCMS (Method F, ES-API): RT 1.99 min, m+H=234; 1H NMR (400MHz, DMSO-d6): δ 8.10 (1H, s), 7.30-7.18 (5H, m), 4.76 (1H, sept, J=6.7Hz), 4.10 (2H, s), 1.43 (6H, d, J=6.7 Hz).

Intermediates 89. Preparation of Sulfonyl Chloride

89a 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride

89b 1-methyl-1H-1,2,3-triazole-5-sulfonyl chloride

89c 1-methyl-1H-1,2,3-triazole-4-sulfonyl chloride

Sulfonyl chlorides of Fractions 1, 2 and 3 from Intermediate 85 wereprepared according to the following preparations:

Preparation 1, Sulfonyl Chloride of Intermediate 85 Fraction 1:N-chlorosuccinimide (3.38 g, 25.3 mmol) was added to a solution ofIntermediate 85 Fraction 1 (1.3 g, 6.33 mmol) in acetic acid (32 mL) andwater (16 mL) and stirred at room temperature for 1 hour. Water (40 mL)was added and the mixture was extracted with ethyl acetate (40 mL). Theorganic phase was washed with saturated aqueous sodium hydrogencarbonate solution (40 mL), brine (40 mL), dried (magnesium sulfate),and solvent removed to give Preparation 1 (1.35 g) as a pale yellow oil.LCMS (Method F, ES-API; quenching into morpholine): RT 1.09 min,m+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl₃): δ 8.11 (1H, s), 4.36(3H, s).

Preparation 2, Sulfonyl Chloride of Intermediate 85 Fraction 2: Chlorinegas was bubbled through a solution of Intermediate 85 Fraction 2 (200mg, 0.974 mmol) in dichloromethane (15 mL) and water (3 mL) for 2minutes at 0° C. then the reaction mixture was stirred at 0° C. for afurther 5 minutes. Water (10 mL) was added and the mixture was extractedwith dichloromethane (10 mL). The organic phase was dried over magnesiumsulfate, filtered and concentrated in vacuo to give Preparation 2 (317mg) as a colourless oil. LCMS (Method F, ES-API; quenching intomorpholine): RT 1.17 min, m+morpholine-Cl=233.1; 1H NMR (400 MHz,CDCl₃): δ 8.27 (1H, s), 4.40 (3H, s).

Preparation 3, Sulfonyl Chloride of Intermediate 85 Fraction 3:N-chlorosuccinimide (2.60 g, 19.49 mmol) was added to a solution ofIntermediate 85 Fraction 3 (1.0 g, 4.87 mmol) in acetic acid (26 mL) andwater (13 mL) and stirred at room temperature for 2 hours. Water (40 mL)was added and the mixture was extracted with ethyl acetate (40 mL). Theorganic phase was washed with saturated aqueous sodium hydrogencarbonate solution (3×40 mL), brine (40 mL), dried (magnesium sulfate),and solvent removed to give Preparation 3 (810 mg) as a colourless oil.LCMS (Method F, ES-API; quenching into morpholine): RT 0.86 min,m+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl₃): δ 8.22 (1H, s), 4.25(3H, s).

The following intermediates 90-92 were similarly prepared fromappropriate starting materials:

Intermediates 90. Preparation of Sulfonyl Chloride

90a 2-ethyl-2H-1,2,3-triazole-4-sulfonyl chloride

90b 1-ethyl-1H-1,2,3-triazole-5-sulfonyl chloride

90c 1-ethyl-1H-1,2,3-triazole-4-sulfonyl chloride

Preparation 1, Sulfonyl Chloride of Intermediate 86 Fraction 1: LCMS(Method F, ES-API; quenching into morpholine): RT 1.37 min,m+morpholine-Cl=247; 1H NMR (400 MHz, CDCl₃): δ 8.11 (1H, s), 4.62 (2H,q, J=7.4 Hz), 1.66 (3H, t, J=7.4 Hz).

Preparation 2, Sulfonyl Chloride of Intermediate 86 Fraction 2: LCMS(Method F, ES-API; quenching into morpholine): RT 1.37 min,m+morpholine-Cl=247; 1H NMR (400 MHz, CDCl₃): δ 8.27 (1H, s), 4.75 (2H,q, J=7.3 Hz), 1.70 (3H, t, J=7.3 Hz).

Preparation 3, Sulfonyl Chloride of Intermediate 86 Fraction 3: LCMS(Method F, ES-API; quenching into morpholine): RT 1.44 min,m+morpholine-Cl=247; 1H NMR (400 MHz, CDCl₃): δ 8.23 (1H, s), 4.56 (2H,q, J=7.4 Hz), 1.67 (3H, t, J=7.4 Hz).

Intermediates 91. Preparation of Sulfonyl Chloride

91a 2-propyl-2H-1,2,3-triazole-4- sulfonyl chloride

91b 1-propyl-1H-1,2,3-triazole-5- sulfonyl chloride

91c 1-propyl-1H-1,2,3-triazole-4- sulfonyl chloride

Preparation 1, Sulfonyl Chloride of Intermediate 87 Fraction 1: LCMS(Method F, ES-API; quenching into morpholine): RT 1.62 min,m+morpholine-Cl=261.2; 1H NMR (400 MHz, CDCl₃): δ 8.11 (1H, s), 4.53(2H, t, J=7.1 Hz), 2.08 (2H, sext, J=7.1 Hz), 0.98 (3H, t, J=7.1 Hz).

Preparation 2, Sulfonyl Chloride of Intermediate 87 Fraction 2: LCMS(Method F, ES-API; quenching into morpholine): RT 1.58 min,m+morpholine-Cl=261.1; 1H NMR (400 MHz, CDCl₃): δ 8.27 (1H, s),4.68-4.64 (2H, m), 2.12 (2H, sext, J=7.1 Hz), 1.05 (3H, t, J=7.1 Hz).

Preparation 3, Sulfonyl Chloride of Intermediate 87 Fraction 3: LCMS(Method F, ES-API; quenching into morpholine): RT 1.38 min,m+morpholine-Cl=261.2; 1H NMR (400 MHz, CDCl₃): δ 8.21 (1H, s), 4.46(2H, t, J=7.1 Hz), 2.04 (2H, sext, J=7.1 Hz), 1.02 (3H, t, J=7.1 Hz).

Intermediates 92. Preparation of Sulfonyl Chloride

92a 2-isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride

92b 1-isopropyl-1H-1,2,3-triazole-5-sulfonyl chloride

92c 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride

Preparation 1, Sulfonyl Chloride of Intermediate 88 Fraction 1: LCMS(Method F, ES-API; quenching into morpholine): RT 1.64 min,m+morpholine-Cl=261; 1H NMR (400 MHz, CDCl₃): δ 7.62 (1H, s), 4.76 (1H,sept., J=6.7 Hz), 1.46 (6H, d, J=6.7 Hz).

Preparation 2, Sulfonyl Chloride of Intermediate 88 Fraction 2: LCMS(Method F, ES-API; quenching into morpholine): RT 1.57 min,m+morpholine-Cl=261; 1H NMR (400 MHz, DMSO-d6): δ 7.60 (1H, s), 5.25(1H, sept., J=6.7 Hz), 1.49 (6H, d, J=6.7 Hz).

Preparation 3, Sulfonyl Chloride of Intermediate 88 Fraction 3: LCMS(Method F, ES-API; quenching into morpholine): RT 1.47 min,m+morpholine-Cl=261; 1H NMR (400 MHz, CDCl₃): δ 8.26 (1H, s), 4.95 (1H,sept., J=6.7 Hz), 1.68 (6H, d, J=6.7 Hz).

Intermediate 93. (R)-methyl1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Made by the method of Intermediate 33, using HCl (4M solution indioxane) in place of trifluoroacetic acid/dichloromethane. LCMS (MethodF, ES-API): RT 2.22 min, m+H=500.

Intermediate 94

Isomer A (R)-methyl 1-(4-fluorophenyl)-6-((2- methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Isomer B (R)-methyl 1-(4-fluorophenyl)-6-((1- methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Isomer C (R)-methyl 1-(4-fluorophenyl)-6-((1- methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

Made from Preparation 1 of Intermediate 89 by the method of Intermediate33, using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.10 min, m+H=473.1.

Intermediate 95

Isomer A (R)-methyl 1-(4- fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4- yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H-pyrazolo[3,4- g]isoquinoline-4a- carboxylate

Isomer B (R)-methyl 1-(4- fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5- yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H-pyrazolo[3,4- g]isoquinoline-4a- carboxylate

Isomer C (R)-methyl 1-(4- fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-4- yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H-pyrazolo[3,4- g]isoquinoline-4a- carboxylate

Made from Preparation 1 of Intermediate 91 by the method of Intermediate33, using HCl (4M solution in dioxane) in place of trifluoroaceticacid/dichloromethane. LCMS (Method F, ES-API): RT 2.40 min, m+H=501.2.

Example 1.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol(3.1 g, 5.3 mmol) in dry dichloromethane (25 mL) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (3.2 g, 7.54mmol; Dess-Martin periodinane) and the reaction mixture stirred for 1hour at room temperature. The reaction mixture was cooled and treatedwith saturated sodium hydrogen carbonate solution (125 mL) followed bydichloromethane (50 mL). The mixture was stirred for 10 minutes and thephases separated. The aqueous phase was extracted with furtherdichloromethane (×2) and the combined organic phases dried over sodiumsulfate. The solids were removed by filtration, the filtrate wasconcentrated under reduced pressure and the residue purified by columnchromatography on silica gel (gradient: 20-30% ethyl acetate incyclohexane) to afford(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a pale yellow foam (2.20 g). The product was further purified bypreparative Hplc (C-18 column eluting with 80% aqueous methanol) to give(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (1.10 g). LCMS (Method D, ESI): RT 5.61 min,m+H=583.0; 1H NMR (400 MHz, CDCl₃): δ 8.62 (ddd, J=4.8, 1.7, 1.0 Hz,1H); 7.85-7.86 (m, 1H); 7.80-7.81 (m, 3H); 7.70 (d, J=8.3 Hz, 2H);7.44-7.45 (m, 3H); 7.27 (s, 1H); 7.16 (t, J=8.5 Hz, 2H); 6.49 (d, J=2.2Hz, 1H); 5.56 (dd, J=12.3, 2.1 Hz, 1H); 4.26 (d, J=16.9 Hz, 1H);3.86-3.89 (m, 1H); 2.83-2.84 (m, 3H); 2.54-2.56 (m, 2H).

Alternative preparation of Example 1: (R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(109.5 g) was suspended with stirring in a 4 N HCl/dioxane solution (250mL) at 20-25° C. After deprotection was complete (1.5 hours) thesolution was concentrated to dryness to give 157.1 g of thecorresponding HCl salt as an amber oil. The salt was suspended indichloromethane (1.5 L) and Hunig's base (150 g, 1150 mmol) was added.When the suspension had cleared a solution of4-(trifluoromethyl)benzenesulfonyl chloride (67.0 g, 275 mmol) indichloromethane (100 mL) was added. The reaction mixture was allowed tostir overnight at 20-25° C., then was quenched with water (500 mL). Theorganic layer was washed with 15% aqueous sodium chloride solution (500mL) and then concentrated. The crude product was purified by columnchromatography on silica gel (300 g), eluting with heptane/ethyl acetate(4:1 to 1:1), to give(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(78 g) as a pale yellow powder.

The following examples were similarly prepared from the appropriateintermediate:

Example 1A.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone

LCMS (method E), Rt=12.56 min (MH)+ 586.2; ¹H NMR (400 MHz, CDCl₃): δ7.82 (d, J=8.2 Hz, 2H); 7.71 (d, J=8.3 Hz, 2H); 7.42-7.43 (m, 2H); 7.31(s, 1H); 7.14-7.15 (m, 3H); 6.97 (s, 1H); 6.53 (d, J=2.3 Hz, 1H); 5.59(dd, J=12.5, 2.1 Hz, 1H); 4.41 (d, J=16.7 Hz, 1H); 3.92-3.95 (m, 1H);3.83 (s, 3H); 2.81-2.82 (m, 3H); 2.57-2.59 (m, 2H).

Example 1B.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-3-yl)methanone

LCMS (Method D, ESI): RT 5.17 min, m+H=583.0; 1H NMR (400 MHz, CDCl₃): δ8.91 (d, J=2.2 Hz, 1H); 8.71 (dd, J=4.8, 1.7 Hz, 1H); 8.01 (dt, J=8.0,2.0 Hz, 1H); 7.94 (d, J=8.2 Hz, 2H); 7.82 (d, J=8.3 Hz, 2H); 7.41-7.42(m, 3H); 7.35 (dd, J=8.0, 4.8 Hz, 1H); 7.18 (t, J=8.5 Hz, 2H); 6.44 (s,1H); 4.60 (dd, J=11.4, 1.9 Hz, 1H); 3.89 (dd, J=10.9, 4.9 Hz, 1H); 3.38(d, J=17.5 Hz, 1H); 2.80 (d, J=17.6 Hz, 1H); 2.55 (d, J=11.4 Hz, 1H);2.48 (td, J=11.5, 3.4 Hz, 1H); 2.26-2.29 (m, 2H).

Example 1C.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method D, ESI): RT 5.50 min, m+H=589.0; 1H NMR (400 MHz, CDCl₃): δ8.00 (d, J=3.1 Hz, 1H); 7.83 (d, J=8.2 Hz, 2H); 7.68-7.69 (m, 3H);7.42-7.43 (m, 2H); 7.29 (s, 1H); 7.17 (t, J=8.5 Hz, 2H); 6.54 (d, J=2.3Hz, 1H); 5.51 (dd, J=12.5, 2.1 Hz, 1H); 4.20 (d, J=16.8 Hz, 1H);3.91-3.95 (m, 1H); 2.85-2.86 (m, 3H); 2.57-2.59 (m, 2H).

Alternative preparation of Example 1c: (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(76.1 g) was deprotected using 4 N HCl/dioxane solution (400 mL) at20-25° C. After reaction was complete (3 h) the solution wasconcentrated to dryness to provide 91.4 g of the corresponding HCl saltas an amber oil. The salt was suspended in dichloromethane (1.0 L) andHunig's base (85.0 g, 650 mmol) was added. When the suspension became aclear solution 4-(trifluoromethyl)benzenesulfonyl chloride (37.2 g, 152mmol) in dichloromethane (100 mL) was added. The mixture was stirredovernight at 20-25° C. The reaction mixture was quenched with water (250mL) and the organic layer washed with 15% aqueous sodium chloridesolution (500 mL) then concentrated. The crude product was purifiedtwice by column chromatography on silica gel (300 g then 800 g), elutingwith heptane/ethyl acetate (3:1), to give(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(54.2 g) as a pale yellow powder.

Example 1D.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone

LCMS (Method D, ESI): RT 5.24 min, m+H=588.0; 1H NMR (400 MHz, CDCl₃): δ7.82-7.84 (m, 4H); 7.40-7.41 (m, 2H); 7.33 (s, 1H); 7.17 (t, J=8.5 Hz,2H); 6.58 (d, J=2.4 Hz, 1H); 5.27 (dd, J=12.9, 2.1 Hz, 1H); 4.14 (d,J=16.8 Hz, 1H); 3.97 (t, J=7.9 Hz, 1H); 2.85-2.87 (m, 2H); 2.75 (d,J=12.9 Hz, 1H); 2.65 (s, 3H); 2.56-2.58 (m, 2H).

Example 1E.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-4-yl)methanone

LCMS (Method D, ESI): RT 5.32 min, m+H=573.0; 1H NMR (400 MHz, CDCl₃): δ7.86 (d, J=8.2 Hz, 2H); 7.76-7.78 (m, 3H); 7.41 (dd, J=8.6, 4.8 Hz, 2H);7.35 (s, 1H); 7.31 (s, 1H); 7.17 (t, J=8.4 Hz, 2H); 6.54 (s, 1H); 5.38(d, J=12.6 Hz, 1H); 4.12 (d, J=16.8 Hz, 1H); 3.91-3.94 (m, 1H);2.82-2.84 (m, 3H); 2.55-2.58 (m, 2H).

Example 1F.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone

LCMS (Method D, ESI): RT 5.35 min, m+H=572.9; 1H NMR (400 MHz, CDCl₃): δ7.86 (d, J=8.2 Hz, 2H); 7.77-7.78 (m, 3H); 7.40-7.41 (m, 2H); 7.35 (d,J=0.7 Hz, 1H); 7.30 (s, 1H); 7.16 (t, J=8.5 Hz, 2H); 6.54 (d, J=2.3 Hz,1H); 5.38 (dd, J=12.6, 2.1 Hz, 1H); 4.12 (d, J=16.8 Hz, 1H); 3.91-3.94(m, 1H); 2.82-2.83 (m, 3H); 2.55-2.57 (m, 2H).

Example 1G.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)methanone

LCMS (Method D, ESI): RT 5.38 min, m+H=571.9; 1H NMR (400 MHz, CDCl₃): δ7.86 (d, J=8.2 Hz, 2H); 7.75 (d, J=8.2 Hz, 2H); 7.57 (dd, J=1.7, 0.8 Hz,1H); 7.41-7.42 (m, 2H); 7.31 (s, 1H); 7.22 (dd, J=3.6, 0.8 Hz, 1H);7.15-7.16 (m, 2H); 6.51-6.52 (m, 2H); 4.96 (dd, J=12.3, 2.0 Hz, 1H);3.86 (dd, J=10.8, 5.6 Hz, 1H); 3.63 (d, J=16.9 Hz, 1H); 2.76-2.78 (m,3H); 2.58-2.60 (m, 1H); 2.47 (d, J=14.8 Hz, 1H).

Example 1H.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(furan-2-yl)methanone

LCMS (Method D, ESI): RT 5.56 min, m+H=587.9; 1H NMR (400 MHz, CDCl₃): δ7.92 (d, J=8.2 Hz, 2H); 7.76-7.78 (m, 3H); 7.61 (dd, J=5.0, 1.1 Hz, 1H);7.45 (dd, J=8.7, 4.7 Hz, 2H); 7.36 (s, 1H); 7.19 (t, J=8.4 Hz, 2H); 7.03(dd, J=5.0, 3.9 Hz, 1H); 6.51 (s, 1H); 4.64 (d, J=11.5 Hz, 1H); 3.87 (d,J=9.1 Hz, 1H); 3.41 (d, J=17.5 Hz, 1H); 2.82 (d, J=17.5 Hz, 1H); 2.67(d, J=11.5 Hz, 1H); 2.56-2.60 (m, 1H); 2.47-2.50 (m, 1H); 2.39 (d,J=13.6 Hz, 1H).

Example 11.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.53 min, m+H=519.1; 1H NMR (400 MHz,CDCl₃): δ 7.82 (1H, d, J=0.6 Hz), 7.55-7.52 (2H, m), 7.44-7.38 (5H, m),7.31 (1H, s), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.3 Hz), 5.40 (1H, dd,J=12.5, 2.0 Hz), 4.12 (1H, d, J=16.9 Hz), 3.91-3.85 (1H, m), 2.92-2.82(2H, m), 2.68 (1H, d, J=12.5 Hz), 2.53-2.42 (5H, m).

Example 1J.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.38 min, m+H=530.2; 1H NMR (400 MHz,CDCl₃): δ 8.92 (2H, d, J=4.8 Hz), 7.49-7.36 (7H, m), 7.32 (1H, s),7-19-7.13 (2H, m), 6.47 (1H, d, J=2.1 Hz), 5.12 (1H, dd, J=12.1, 2.0Hz), 4.13 (1H, d, J=16.9 Hz), 3.80-3.76 (1H, m), 2.95 (1H, d, J=16.9Hz), 2.88-2.79 (1H, m), 2.61 (1H, d, J=12.2 Hz), 2.46-2.37 (5H, m).

Example 1K.(R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.78 min, m+H=581.2; 1H NMR (400 MHz,CDCl₃): δ 8.46 (1H, d, J=4.9 Hz), 7.45-7.39 (3H, m), 7.29 (1H, s),7.21-7.14 (4H, m), 7.00-6.95 (2H, m), 6.49 (1H, s), 5.63-5.60 (1H, m),4.30 (1H, dd, J=16.9, 2.1 Hz), 3.88-3.83 (4H, m), 2.89-2.78 (3H, m),2.63-2.57 (1H, m), 2.53-2.49 (1H, m).

Example 1L.(R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone

LCMS (Method F, ES-API): RT 3.19 min, m+H=597.2; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, dd, J=4.9, 0.6 Hz), 7.70 (1H, m), 7.45-7.41 (2H, m),7.33-7.30 (4H, m), 7.19-7.14 (2H, m), 6.50 (1H, d, J=2.0 Hz), 5.58 (1H,dd, J=12.5, 2.0 Hz), 4.24 (1H, d, J=16.9 Hz), 3.91-3.86 (1H, m),2.92-2.80 (3H, m), 2.73-2.67 (3H, m), 2.56-2.51 (1H, m), 1.27 (3H, t,J=7.5 Hz).

Example 1M.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methoxypyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.97 min, m+H=599.2; 1H NMR (400 MHz,CDCl₃): δ 8.42 (1H, d, J=4.9 Hz), 7.45-7.41 (2H, m), 7.37 (1H, d, J=2.5Hz), 7.33-7.30 (2H, m), 7.27 (1H, s), 7.19-7.14 (2H, m), 6.97 (1H, dd,J=5.8, 2.5 Hz), 6.50 (1H, d, J=2.0 Hz), 5.58 (1H, dd, J=12.1, 2.0 Hz),4.28 (1H, d, J=16.9 Hz), 3.91-3.85 (4H, m), 2.91-2.78 (3H, m), 2.70-2.63(1H, m), 2.55-2.50 (1H, m).

Example 2.(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of(R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanonein dichloromethane (2.5 ml) (2.7 mL, ˜0.2 mmol) containingdisiopropylethylamine (174 μL, 1 mmol) was added to 4-fluoro-phenylsulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 μL,0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixturewas concentrated under reduced pressure and the residue was purified bycolumn chromatography on silica gel (gradient: 20-30% ethyl acetate incyclohexane) to afford(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m+H=533.0;1H NMR (400 MHz, CDCl₃): δ 8.62-8.63 (m, 1H); 7.85-7.86 (m, 2H);7.69-7.70 (m, 2H); 7.44-7.45 (m, 3H); 7.28 (s, 1H); 7.14 (dt, J=12.9,8.5 Hz, 4H); 6.48 (d, J=2.2 Hz, 1H); 5.51 (dd, J=12.2, 2.1 Hz, 1H); 4.29(d, J=16.9 Hz, 1H); 3.82-3.86 (m, 1H); 2.84-2.86 (m, 2H); 2.72 (d,J=12.2 Hz, 1H); 2.46-2.51 (m, 2H).

The following examples were similarly prepared from the appropriateintermediate:

Example 2A.(R)-(6-((3-fluorobenzyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.48 min, m+H=552.9; 1H NMR (400 MHz,CDCl₃): δ 8.07 (1H, d, J=3.1 Hz), 7.68 (1H, d, J=3.1 Hz), 7.47-7.41 (2H,m), 7.35-7.30 (2H, m), 7.20-7.14 (2H, m), 7.09-7.04 (3H, m), 6.53 (1H,s), 5.43 (1H, dd, J=7.1, 2.0 Hz), 4.23 (1H, d, J=16.8 Hz), 4.08 (1H, d,J=13.8 Hz), 4.02 (1H, d, J=13.8 Hz), 3.61-3.59 (1H, m), 3.07 (1H, d,J=13.1 Hz), 2.85 (1H, d, J=16.8 Hz), 2.73-2.64 (2H, m), 2.45-2.37 (1H,m).

Example 2B.((4aR)-1-(4-fluorophenyl)-6-((((R/S)-tetrahydrofuran-2-yl)methyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.28 min, m+H=528.9; 1H NMR (400 MHz,CDCl₃): δ 8.07-8.06 (1H, m), 7.66 (1H, d, J=2.9 Hz), 7.48-7.44 (2H, m),7.33 (1H, s), 7.20-7.14 (2H, m), 6.57 (1H, s), 5.47 (1H, ddd, J=17.5,13.1, 2.2 Hz), 4.32-4.10 (2H, m), 3.88-3.72 (3H, m), 3.25 (1H, dd,J=43.6, 13.4 Hz), 3.13-2.81 (5H, m), 2.56-2.50 (1H, m), 2.40 (1H, s),2.13-2.02 (1H, m), 1.91-1.84 (2H, m).

Example 2C.(R)-(1-(4-fluorophenyl)-6-(o-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.61 min, m+H=528.8; 1H NMR (400 MHz,CDCl₃): δ 8.34 (1H, ddd, J=4.7, 1.8, 0.8 Hz), 7.85 (1H, dd, J=7.6, 1.5Hz), 7.81-7.79 (1H, m), 7.65 (1H, dt, J=7.6, 1.8 Hz), 7.46-7.41 (2H, m),7.32 (1H, ddd, J=7.6, 4.8, 1.4 Hz), 7.24-7.14 (5H, m), 6.93-6.91 (1H,m), 6.52 (1H, s), 5.49 (1H, dd, J=12.8, 2.1 Hz), 4.20 (1H, d, J=16.9Hz), 3.98-3.95 (1H, m), 3.08 (1H, d, J=12.8 Hz), 2.90-2.82 (3H, m),2.60-2.54 (1H, m), 2.34 (3H, s).

Example 2D.(R)-(6-((4-ethylpheny)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.75 min, m+H=542.8; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.89 (1H, m), 7.84(1H, dt, J=7.5, 1.8 Hz), 7.61-7.58 (2H, m), 7.47 (1H, ddd, J=7.5, 4.7,1.4 Hz), 7.44-7.40 (2H, m), 7.27-7.22 (3H, m), 7.19-7.13 (2H, m), 6.46(1H, d, J=2.1 Hz), 5.50 (1H, dd, J=12.4, 2.1 Hz), 4.31 (1H, d, J=16.9Hz), 3.84-3.79 (1H, m), 2.91-2.77 (2H, m), 2.72-2.65 (3H, m), 2.47-2.38(2H, m), 1.25 (3H, t, J=7.5 Hz).

Example 2E.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.62 min, m+H=528.8; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.89 (1H, m), 7.84(1H, dt, J=7.4, 1.7 Hz), 7.50-7.40 (5H, m), 7.36-7.34 (2H, m), 7.29 (1H,s), 7.19-7.13 (2H, m), 6.47 (1H, d, J=2.1 Hz), 5.51 (1H, dd, J=12.4, 2.1Hz), 4.31 (1H, d, J=16.9 Hz), 3.84-3.80 (1H, m), 2.92-2.78 (2H, m), 2.68(1H, d, J=12.4 Hz), 2.49-2.40 (5H, m).

Example 2F.(R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.68 min, m+H=548.8; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84(1H, dt, J=7.5, 1.8 Hz), 7.66-7.65 (1H, m), 7.59-7.56 (1H, m), 7.52-7.47(2H, m), 7.46-7.41 (3H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.49 (1H,d, J=2.1 Hz), 5.55 (1H, dd, J=12.2, 2.1 Hz), 4.29 (1H, d, J=16.9 Hz),3.87-3.82 (1H, m), 2.92-2.75 (3H, m), 2.56-2.47 (2H, m).

Example 2G.(R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.60 min, m+H=545.2; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.83(1H, dt, J=7.5, 1.8 Hz), 7.49-7.36 (4H, m), 7.29 (2H, m), 7.19-7.13 (3H,m), 7.05 (1H, ddd, J=8.3, 2.5, 0.9 Hz), 6.47 (1H, d, J=2.1 Hz), 5.50(1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d, J=16.9 Hz), 3.85-3.80 (4H, m),2.91-2.78 (2H, m), 2.72 (1H, d, J=12.2 Hz), 2.51-2.44 (2H, m).

Example 211.(R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.78 min, m+H=567.1; 1H NMR (400 MHz,CDCl₃): δ 8.63-8.61 (1H, m), 7.89-7.82 (2H, m), 7.50-7.41 (6H, m), 7.28(1H, s), 7.19-7.13 (2H, m), 6.50 (1H, d, J=2.1 Hz), 5.54 (1H, dd,J=12.2, 2.1 Hz), 4.27 (1H, d, J=16.9 Hz), 3.89-3.85 (1H, m), 2.90-2.79(3H, m), 2.61-2.49 (2H, m).

Example 21.(R)-(1-(4-fluorophenyl)-6-((4-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=545.2; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.83(1H, dt, J=7.6, 1.8 Hz), 7.64-7.60 (2H, m), 7.48-7.40 (3H, m), 7.29 (1H,s), 7.19-7.13 (2H, m), 6.93-6.89 (2H, m), 6.47 (1H, d, J=2.1 Hz), 5.48(1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d, J=16.9 Hz), 3.85-3.79 (4H, m),2.90-2.77 (2H, m), 2.65 (1H, d, J=12.2 Hz), 2.48-2.39 (2H, m).

Example 2J.(R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.74 min, m+H=547.2; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84(1H, dt, J=7.6, 1.8 Hz), 7.49-7.40 (3H, m), 7.37 (1H, dd, J=8.1, 2.1Hz), 7.33-7.26 (3H, m), 7.19-7.13 (2H, m), 6.48 (1H, d, J=2.1 Hz), 5.52(1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d, J=16.9 Hz), 3.85-3.80 (1H, m),2.91-2.77 (2H, m), 2.71 (1H, d, J=12.2 Hz), 2.51-2.44 (2H, m), 2.31 (3H,d, J=1.7 Hz).

Example 2K.(R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=515.2; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.92-7.89 (1H, m), 7.84(1H, dt, J=7.6, 1.8 Hz), 7.71-7.68 (2H, m), 7.58-7.53 (1H, m), 7.50-7.40(5H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.47 (1H, d, J=2.1 Hz), 5.53(1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.85-3.81 (1H, m),2.91-2.78 (2H, m), 2.67 (1H, d, J=12.2 Hz), 2.48-2.40 (2H, m).

Example 2L.(R)-(1-(4-fluorophenyl)-6-((2-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.85-7.82 (1H, m), 7.80(1H, dt, J=7.6, 1.8 Hz), 7.73-7.68 (1H, m), 7.52-7.41 (4H, m), 7.28 (1H,s), 7.19-7.10 (4H, m), 6.50 (1H, d, J=2.1 Hz), 5.60 (1H, dd, J=12.2, 2.1Hz), 4.29 (1H, d, J=16.9 Hz), 3.97-3.93 (1H, m), 3.01 (1H, dd, J=12.8.1.2 Hz), 2.91-2.72 (3H, m), 2.52-2.48 (1H, m).

Example 2M.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.17 min, m+H=519.1; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.89 (1H, m), 7.84(1H, dt, J=7.6, 1.8 Hz), 7.68-7.65 (2H, m), 7.49-7.42 (3H, m), 7.30 (1H,s), 7.20-7.14 (2H, m), 6.49 (1H, d, J=2.1 Hz), 5.46 (1H, dd, J=12.2, 2.1Hz), 4.31 (1H, d, J=16.9 Hz), 3.91 (3H, s), 3.80-3.76 (1H, m), 2.91 (1H,d, J=16.9 Hz), 2.88-2.79 (1H, m), 2.68 (1H, d, J=12.2 Hz), 2.50-2.41(2H, m).

Example 2N.(R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.65 min, m+H=584.1; 1H NMR (400 MHz,CDCl₃): δ 8.97 (1H, d, J=2.2 Hz), 8.63-8.61 (1H, m), 8.14 (1H, dd,J=8.3, 2.2 Hz), 7.85-7.82 (2H, m), 7.73 (1H, d, J=8.3 Hz), 7.51-7.46(1H, m), 7.44-7.40 (2H, m), 7.27 (1H, s), 7.20-7.14 (2H, m), 6.50 (1H,d, J=2.1 Hz), 5.62 (1H, dd, J=12.2, 2.1 Hz), 4.22 (1H, d, J=16.9 Hz),3.96-3.92 (1H, m), 2.93 (1H, d, J=12.6 Hz), 2.90-2.80 (2H, m), 2.73-2.66(1H, m), 2.56-2.53 (1H, m).

Example 20.(R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.68 min, m+H=529.2; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.83(1H, dt, J=7.6, 1.8 Hz), 7.58-7.56 (2H, m), 7.49-7.40 (3H, m), 7.29 (1H,s), 7.26-7.24 (2H, m), 7.19-7.13 (2H, m), 6.46 (1H, d, J=2.1 Hz), 5.49(1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.84-3.79 (1H, m),2.90-2.77 (2H, m), 2.65 (1H, dd, J=12.8. 1.2 Hz), 2.47-2.38 (5H, m).

Example 2P.(R)-(6-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.78 min, m+H=601.1; 1H NMR (400 MHz,CDCl₃): δ 8.62-8.60 (1H, m), 7.94 (1H, dd, J=6.6, 2.2 Hz), 7.90-7.80(3H, m), 7.49-7.39 (1H, m), 7.44-7.40 (2H, m), 7.27 (1H, s), 7.26-7.22(1H, m), 7.20-7.13 (2H, m), 6.50 (1H, d, J=2.1 Hz), 5.55 (1H, dd,J=12.2, 2.1 Hz), 4.24 (1H, d, J=16.9 Hz), 3.91-3.87 (1H, m), 2.90-2.80(3H, m), 2.65-2.59 (1H, m), 2.55-2.50 (1H, m).

Example 2Q.(R)-4-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS (Method F, ES-API): RT 2.49 min, m+H=540.0; 1H NMR (400 MHz,CDCl₃): δ 8.63-8.61 (1H, m), 7.87-7.83 (2H, m), 7.82-7.77 (2H, m),7.73-7.70 (2H, m), 7.49 (1H, ddd, J=6.2, 4.8, 2.7 Hz), 7.44-7.39 (2H,m), 7.27 (1H, m), 7.18-7.12 (2H, m), 6.49 (1H, d, J=2.0 Hz), 5.56 (1H,dd, J=12.3, 2.0 Hz), 4.24 (1H, d, J=16.9 Hz), 3.89-3.85 (1H, m),2.88-2.79 (3H, m), 2.61-2.49 (2H, m).

Example 2R.(R)-(1-(4-fluorophenyl)-6-((6-methoxypyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.52 min, m+H=546.0; 1H NMR (400 MHz,CDCl₃): δ 8.61 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 8.49 (1H, dd, J=2.5, 0.6Hz), 7.89-7.79 (2H, m), 7.76 (1H, dd, J=8.8, 2.5 Hz), 7.47-7.41 (3H, m),7.28 (1H, s), 7.18-7.13 (2H, m), 6.71 (1H, dd, J=8.8, 0.6 Hz), 6.49 (1H,d, J=2.1 Hz), 5.52 (1H, dd, J=12.2, 2.1 Hz), 4.27 (1H, d, J=16.9 Hz),3.98 (3H, s), 3.90-3.82 (1H, m), 2.90-2.75 (3H, m), 2.58-2.48 (2H, m).

Example 2S.(R)-(1-(4-fluorophenyl)-6-((tetrahydro-211-pyran-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.21 min, m+H=523.2; 1H NMR (400 MHz,CDCl₃): δ 8.69-8.68 (1H, m), 7.90-7.88 (1H, m), 7.84 (1H, dt, J=7.4, 1.8Hz), 7.52-7.42 (3H, m), 7.29 (1H, s), 7.21-7.15 (2H, m), 6.52 (1H, d,J=2.1 Hz), 5.60 (1H, dd, J=12.2, 2.1 Hz), 4.20 (1H, d, J=16.9 Hz),4.00-3.83 (4H, m), 3.28 (1H, d, J=12.9 Hz), 3.15 (1H, dt, J=11.9, 2.5Hz), 3.05-2.98 (2H, m), 2.91 (1H, d, J=16.9 Hz), 2.84-2.74 (1H, m),2.55-2.51 (1H, m), 1.84-1.65 (4H, m).

Example 2T.(R)-(6-(cyclohexylsulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.65 min, m+H=521.1; 1H NMR (400 MHz,CDCl₃): δ 8.68 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.90 (1H, dt, J=7.8, 1.2Hz), 7.84 (1H, td, J=7.5, 1.8 Hz), 7.50-7.43 (3H, m), 7.29 (1H, s),7.21-7.15 (2H, m), 6.53 (1H, d, J=2.1 Hz), 5.59 (1H, dd, J=13.1, 1.9Hz), 4.26 (1H, d, J=16.9 Hz), 3.86-3.80 (1H, m), 3.26 (1H, d, J=13.2Hz), 2.98 (1H, td, J=12.4, 3.2 Hz), 2.92 (1H, d J=16.9 Hz), 2.78 (1H,tdd, J=14.8, 5.8, 2.1 Hz), 2.64 (1H, tt, J=12.3, 3.3 Hz), 2.51 (1H, dt,J=14.7, 2.3 Hz), 2.02-1.95 (1H, m), 1.84-0.85 (9H, m).

Example 2U.(R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.67 min, m+H=601.2; 1H NMR (400 MHz,CDCl₃): δ 8.81 (1H, d, J=4.9 Hz), 8.13 (1H, m), 7.71-7.69 (1H, m),7.47-7.42 (2H, m), 7.40 (1H, d, J=2.0 Hz), 7.28 (1H, s), 7.21-7.15 (2H,m), 6.59 (1H, d, J=2.0 Hz), 6.55 (1H, d, J=1.6 Hz), 5.52 (1H, dd,J=12.6, 2.0 Hz), 4.35-4.23 (2H, m), 4.18 (1H, d, J=16.9 Hz), 3.92-3.87(1H, m), 3.02 (1H, d, J=12.8 Hz), 2.92 (1H, d, J=16.9 Hz), 2.89-2.74(2H, m), 2.59-2.55 (1H, m), 1.40 (3H, t, J=7.3 Hz).

Example 2V.(R)-(6-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.37 min, m+H=601.3; 1H NMR (400 MHz,CDCl₃): δ 8.79 (1H, d, J=4.9 Hz), 8.12 (1H, m), 7.67 (1H, dd, J=4.9, 1.0Hz), 7.47-7.42 (2H, m), 7.27 (1H, s), 7.21-7.15 (2H, m), 6.53 (1H, d,J=2.1 Hz), 5.42 (1H, dd, J=12.3, 2.0 Hz), 4.19 (1H, d, J=16.9 Hz),3.87-3.83 (1H, m), 2.93 (1H, d, J=16.9 Hz), 2.91 (1H, d, J=12.8 Hz),2.85-2.80 (1H, m), 2.72-2.76 (1H, m), 2.56-2.52 (1H, m), 2.32 (6H, s).

Example 2W.(R)-(6-((1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.18 min, m+H=573.2; 1H NMR (400 MHz,CDCl₃): δ 10.27 (1H, br s), 8.84 (1H, d, J=4.9 Hz), 8.13 (1H, m), 7.67(1H, dd, J=4.9, 1.0 Hz), 7.64 (1H, s), 7.49 (1H, s), 7.46-7.41 (2H, m),7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.55 (1H, dd,J=12.6, 2.0 Hz), 4.22 (1H, d, J=16.9 Hz), 3.88-3.84 (1H, m), 3.01 (1H,d, J=12.7 Hz), 2.94 (1H, d, J=16.9 Hz), 2.86-2.77 (1H, m), 2.71-2.64(1H, m), 2.50-2.47 (1H, m).

Example 3.(R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(80 mg, 0.14 mmol) and morpholine (150 μL, 1.73 mmol) in acetonitrile(2.5 mL) was heated at 100° C. for 70 minutes in a microwave reactor.The reaction mixture was concentrated and the residue purified by columnchromatography on silica gel (gradient: 30-60% ethyl acetate incyclohexane) to afford(R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a colourless glass (70 mg). LCMS (Method D, ESI): RT 4.94 min,m+H=601.0; 1H NMR (400 MHz, CDCl₃): δ 8.63 (ddd, J=4.8, 1.7, 0.9 Hz,1H); 8.44 (d, J=2.5 Hz, 1H); 7.84-7.85 (m, 2H); 7.66 (dd, J=9.1, 2.5 Hz,1H); 7.44-7.45 (m, 3H); 7.29 (s, 1H); 7.16 (t, J=8.5 Hz, 2H); 6.49-6.50(m, 2H); 5.49 (dd, J=12.1, 2.1 Hz, 1H); 4.28 (d, J=16.9 Hz, 1H); 3.80(t, J=4.8 Hz, 5H); 3.63 (t, J=4.8 Hz, 4H); 2.83-2.85 (m, 2H); 2.71 (d,J=12.1 Hz, 1H); 2.47-2.50 (m, 2H).

Example 4.(R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

A mixture of(R)-(6-(6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(100 mg, 0.180 mmol) and pyrrolidine (37.5 μL, 0.450 mmol) inacetonitrile (2 mL) was stirred at 40° C. for 0.5 hour. The reactionmixture was cooled to room temperature and concentrated in vacuo to givea yellow oil. The crude product was purified by column chromatography onsilica gel (gradient: 0-100% ethyl acetate in isohexane) to give a whitesolid. This was further purified by preparative HPLC (Gilson, Acidic(0.1% Formic acid), Agilent Prep C-18, 5 μm, 21.2×50 mm column, 30-95%acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanoneas a white solid (51 mg). LCMS (Method F, ES-API): RT 2.43 min,m+H=590.9; 1H NMR (400 MHz, CDCl₃): δ 8.45 (1H, dd, J=2.0, 0.5 Hz), 8.01(1H, d, J=3.1 Hz), 7.63-7.59 (2H, m), 7.46-7.41 (2H, m), 7.29 (1H, s),7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 6.27 (1H, d, J=9.1 Hz), 5.47(1H, dd, J=12.2, 2.1 Hz), 4.20 (1H, d, J=16.8 Hz), 3.87-3.83 (1H, m),2.91-2.82 (2H, m), 2.71 (1H, d, J=12.3 Hz), 2.53-2.46 (2H, m), 2.06-2.04(4H, m), 1.33-1.24 (2H, m), 1.17-1.07 (2H, m).

Example 5.(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(0.25 g, 0.520 mmol) in dichloromethane (8 mL) and trifluoroacetic acid(2 mL) was stirred at room temperature for 90 minutes, then evaporated,azeotroping twice with toluene to give a brown oil. This material wasre-dissolved in dichloromethane (8 mL), and diisopropylethylamine (0.454mL, 2.60 mmol) was added, followed by 4-fluorobenzene-1-sulfonylchloride (0.121 g, 0.624 mmol), and the reaction mixture stirred at roomtemperature for 48 hours. The reaction mixture was then evaporated invacuo and the residue purified by column chromatography on silica gel(gradient: 0 to 40% ethyl acetate in isohexane) to give a white solid(204 mg). 80 mg of this sample was purified by preparative HPLC (Varian,Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mmcolumn, 25-80% acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanoneas a pale yellow solid (45 mg). LCMS (Method F, ES-API): RT 2.58 min,m+H=538.9; 1H NMR (400 MHz, CDCl₃): δ 8.02 (d, 1H, J=3.1 Hz), 7.75-7.70(m, 2H), 7.68 (d, 1H, J=3.1 Hz), 7.45-7.40 (m, 2H), 7.29 (s, 1H),7.20-7.11 (m, 4H), 6.53 (d, 1H, J=2.2 Hz), 5.49 (dd, 1H, J=12.3, 2.0Hz), 4.20 (d, 1H, J=16.8 Hz), 3.93-3.86 (m, 1H), 2.94-2.83 (m, 2H), 2.74(d, 1H, J=12.4 Hz), 2.57-2.47 (m, 2H).

The following examples were similarly prepared from the appropriateintermediates:

Example 5A.(R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.59 min, m+H=539.0; 1H NMR (400 MHz,CDCl₃): δ 8.06 (d, 1H, J=3.2 Hz), 7.67 (d, 1H, J=3.1 Hz), 7.53-7.45 (m,2H), 7.45-7.39 (m, 3H), 7.30 (s, 1H), 7.29-7.23 (m, 1H), 7.19-7.13 (m,2H), 6.53 (d, 1H, J=2.1 Hz), 5.53 (dd, 1H, J=12.2, 1.7 Hz), 4.22 (d, 1H,J=17.1 Hz), 3.92-3.86 (m, 1H), 2.94-2.81 (m, 2H), 2.76 (d, 1H, J=12.2Hz), 2.58-2.49 (m, 2H).

Example 5B.(R)-4-0(1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)methyl)benzonitrile

LCMS (Method F, ES-API): RT 2.36 min, m+H=560; 1H NMR (400 MHz, CDCl₃):δ 8.07 (d, 1H, J=3.1 Hz), 7.66 (d, 1H, J=3.1 Hz) 7.45-7.43 (m, 2H),7.46-7.41 (m, 5H), 7.32 (s, 1H), 7.20-7.16 (m, 2H), 6.55 (s, 1H), 5.47(dd, 1H, J=13.5, 2.0 Hz), 4.20 (d, 1H, J=20 Hz), 4.13-4.06 (m, 2H), 3.12(d, 1H, J=16 Hz), 2.86 (d, 1H, J=20 Hz), 2.70-2.50 (m, 2H), 2.44 (m,1H).

Example 5C.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.73 min, m+H=583.2; 1H NMR (400 MHz,CDCl₃): 6.65-8.64 (1H, m), 7.94 (1H, m), 7.89-7.78 (4H, m), 7.63-7.59(1H, m), 7.47 (1H, ddd, J=7.3, 4.8, 1.5 Hz), 7.44-7.40 (2H, m), 7.28(1H, s), 7.19-7.13 (2H, m), 6.48 (1H, d, J=2.2 Hz), 5.56 (1H, dd,J=12.4, 2.2 Hz), 4.26 (1H, d, J=16.9 Hz), 3.89-3.85 (1H, m), 2.91-2.79(3H, m), 2.58-2.48 (2H, m).

Example 5D.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-1,2,4-triazol-5-yl)methanone

LCMS (Method F, ES-API): RT 2.60 min, m+H=587.2; 1H NMR (400 MHz,CDCl₃): δ 7.99 (1H, d, J=1.3 Hz), 7.83-7.81 (2H, m), 7.78-7.76 (2H, m),7.44-7.41 (2H, m), 7.33 (1H, s), 7.19-7.15 (2H, m), 6.56 (1H, s), 5.36(1H, d, J=12.8 Hz), 4.32 (1H, d, J=17.1 Hz), 4.09 (3H, s), 3.96-3.92(1H, m), 2.89-2.79 (2H, m), 2.71 (1H, d, J=12.8 Hz), 2.57-2.50 (2H, m).

Example 5E.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrazin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.59 min, m+H=583.8; 1H NMR (400 MHz,CDCl₃): δ 9.10 (1H, d, J=1.7 Hz), 8.79 (1H, d, J=2.3 Hz), 8.62 (1H, dd,J=2.3, 1.7 Hz), 7.83-7.81 (2H, m), 7.77-7.75 (2H, m), 7.44-7.41 (2H, m),7.29 (1H, s), 7.20-7.15 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.39 (1H, dd,J=12.4, 2.3 Hz), 4.12 (1H, d, J=16.9 Hz), 3.90-3.85 (1H, m), 2.92-2.88(2H, m), 2.72 (1H, d, J=12.4 Hz), 2.52-2.45 (2H, m).

Example 5F.(R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.35 min, m+H=534.2; 1H NMR (400 MHz,CDCl₃): δ 8.73 (1H, m), 8.67-8.65 (1H, m), 8.60 (1H, d, J=2.8 Hz),7.89-7.82 (2H, m), 7.65 (1H, ddd, J=7.6, 2.8, 1.8 Hz), 7.49 (1H, ddd,J=6.8, 4.8, 1.8 Hz), 7.45-7.40 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H, m),6.51 (1H, d, J=2.1 Hz), 5.60 (1H, dd, J=12.4, 2.1 Hz), 4.26 (1H, d,J=16.9 Hz), 3.92-3.88 (1H, m), 2.91-2.79 (3H, m), 2.67-2.61 (1H, m),2.55-2.50 (1H, m).

Example 5G.(R)-(1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.56 min, m+H=532.8; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.85(1H, dt, J=7.4, 1.7 Hz), 7.50-7.36 (6H, m), 7.29 (1H, s), 7.27-7.22 (1H,m), 7.19-7.13 (2H, m), 6.48 (1H, d, J=2.1 Hz), 5.55 (1H, dd, J=12.4, 2.1Hz), 4.30 (1H, d, J=16.9 Hz), 3.86-3.81 (1H, m), 2.91-2.73 (3H, m),2.54-2.47 (2H, m).

Example 5H.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methoxypyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.76 min, m+H=613.2; 1H NMR (400 MHz,CDCl₃): δ 8.72 (1H, dd, J=2.5, 0.6 Hz), 8.06 (1H, dd, J=8.8, 2.5 Hz),7.95-7.93 (2H, m), 7.81-7.79 (2H, m), 7.47-7.42 (2H, m), 7.41 (1H, s),7.22-7.16 (2H, m), 6.72 (1H, dd, J=8.8, 0.6 Hz), 6.44 (1H, s), 4.59 (1H,dd, J=11.1, 1.7 Hz), 3.96 (3H, s), 3.90-3.86 (1H, m), 3.73 (1H, d,J=17.8 Hz), 2.79 (1H, d, J=17.8 Hz), 2.56 (1H, d, J=11.1 Hz), 2.53-2.46(1H, m), 2.31-2.20 (2H, m).

Example 5I.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-5-yl)methanone

LCMS (Method F, ES-API): RT 2.56 min, m+H=589.1; 1H NMR (400 MHz,CDCl₃): δ 8.95 (1H, d, J=0.5 Hz), 8.48 (1H, d, J=0.5 Hz), 7.94-7.92 (2H,m), 7.81-7.79 (2H, m), 7.47-7.42 (2H, m), 7.37 (1H, s), 7.23-7.17 (2H,m), 6.55 (1H, s), 4.62 (1H, dd, J=11.5, 1.9 Hz), 3.93-3.88 (1H, m), 3.34(1H, d, J=17.6 Hz), 2.83 (1H, d, J=17.6 Hz), 2.61 (1H, d, J=11.5 Hz),2.58-2.42 (3H, m).

Example 5J.(R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.35 min, m+H=540.

Example 6.(R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

A solution of pyrrolidine (0.046 mL, 0.557 mmol) and(R)-(1-(4-fluorophenyl)-6-(4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(0.1 g, 0.186 mmol) in N-methylpyrrolidine (2 mL) was stirred at 50° C.in a sealed vial for 6 hours, then allowed to stand at room temperaturefor 72 hours. The reaction mixture was then stirred at 100° C. for anadditional 5 hours, cooled to room temperature, and purified directly bypreparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-SelectPrep-C18, 5 19×50 mm column, 50-70% acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanoneas a pale yellow solid (58 mg). LCMS (Method F, ES-API): RT 2.81 min,m+H=590.0; 1H NMR (400 MHz, CDCl₃): δ 8.02 (d, 1H, J=3.1 Hz), 7.62 (d,1H, J=3.1 Hz), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H),7.219-7.12 (m, 2H), 6.50-6.45 (m, 3H), 5.46 (dd, 1H, J=12.1, 2.0 Hz),4.21 (d, 1H, J=16.8 Hz), 3.86-3.80 (m, 1H), 3.35-3.30 (m, 4H), 2.92-2.81(m, 2H), 2.64 (d, 1H, J=12.2 Hz), 2.52-2.36 (m, 2H), 2.07-2.01 (m, 4H).

The following examples were similarly prepared from the appropriateintermediate:

Example 6A.(R)-(1-(4-fluorophenyl)-6-3-((pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.88 min, m+H=590.1; 1H NMR (400 MHz,CDCl₃): δ 8.04 (d, 1H, J=2.8 Hz), 7.63 (d, 1H, J=3.2 Hz), 7.45-7.40 (m,2H), 7.33-7.24 (m, 3H), 7.19-7.10 (m, 2H), 6.99-6.94 (m, 1H), 6.65 (dt,1H, J=8.0, 2.3 Hz), 6.50 (d, 1H, J=2.4 Hz), 5.46 (dd, 1H, J=12.7, 2.1Hz), 4.22 (d, 1H, J=16.6 Hz), 3.91-3.81 (m, 1H), 3.33-3.23 (m, 4H),2.94-2.83 (m, 2H), 2.76 (d, 1H, J=12.4 Hz), 2.54-2.46 (m, 2H), 2.06-2.01(m, 4H).

Example 7.(R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

A mixture of(R)-(1-(4-fluorophenyl)-6-(5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(100 mg, 0.185 mmol) and piperidine (47 mg, 0.56 mmol) inN-methylpyrrolidine (1 mL) was heated at 100° C. for 6 hours. Themixture was cooled and the reaction mixture was purified by preparativeHPLC (Gilson, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 5-95% acetonitrile in water) to give(R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanoneas a white solid (35 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=605;1H NMR (400 MHz, CDCl₃): δ 8.39 (d, 1H, J=3.0 Hz), 8.27 (d, 1H, J=2.0Hz), 8.05 (d, 1H, J=3.0 Hz), 7.65 (d, 1H, J=3.0 Hz), 7.54-7.41 (m, 2H),7.31-7.30 (m, 2H). 7.19-7.14 (m, 2H), 6.53 (d, 1H, J=2.0 Hz), 5.51 (dd,1H, J=12.0, 2.0 Hz), 4.21 (d, 1H, J=17.0 Hz), 3.90-3.86 (m, 1H),3.27-3.25 (m, 4H), 2.91-2.81 (m, 3H), 2.61-2.52 (m, 2H), 1.75-1.56 (m,6H).

The following examples were similarly prepared from the appropriateintermediate:

Example 7A.(R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.49 min, m+H=591; 1H NMR (400 MHz, CDCl₃):δ 8.18 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=3.0 Hz), 8.04 (1H, d, J=3.0Hz), 7.65 (1H, d, J=3.0 Hz), 7.43 (2H, dd, J=9.0, 5.0 Hz), 7.29 (1H, s),7.19-7.14 (2H, m), 6.95-6.93 (1H, m), 6.53 (1H, d, J=2.0 Hz), 5.50 (1H,dd, J=12.0, 2.0 Hz), 4.2 (1H, d, J=17.0 Hz), 3.92-3.88 (1H, m),3.33-3.28 (4H, m), 2.90-2.82 (3H, m), 2.62-2.51 (2H, m), 2.09-2.04 (4H,m).

Example 8.(R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(100 mg, 0.182 mmol) and pyrrolidine (37.9 μl, 0.455 mmol) inacetonitrile (2 mL) was stirred in a sealed vial at 40° C. for 1 hour.The cooled reaction mixture was then purified directly by preparativeHPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 5-95% acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas a white solid (29 mg). LCMS (Method F, ES-API): RT 2.48 min,m+H=585.3; 1H NMR (400 MHz, CDCl₃): δ 8.63-8.61 (1H, m), 8.43 (1H, d,J=2.4 Hz), 7.89-7.87 (1H, m), 7.80 (1H, dt, J=7.6, 1.8 Hz), 7.58 (1H,dd, J=9.0, 2.4 Hz), 7.45-7.41 (3H, m), 7.28 (1H, s), 7.19-7.13 (2H, m),6.47 (1H, d, J=2.1 Hz), 6.22 (1H, d, J=9.0 Hz), 5.46 (1H, dd, J=12.2,2.1 Hz), 4.27 (1H, d, J=16.9 Hz), 3.83-3.79 (1H, m), 3.52-3.45 (4H, m),2.90-2.76 (2H, m), 2.68 (1H, d, J=12.3 Hz), 2.51-2.45 (2H, m), 2.06-2.04(4H, m).

Example 9.((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

A mixture of(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(92 mg, 0.165 mmol) and (R)-3-fluoropyrrolidine.HCl (41.6 mg, 0.331mmol) in N,N-dimethylformamide (2 mL) was stirred in a sealed vial at40° C. for 1 hour, then at 55° C. for a further 2 hours. The cooledreaction mixture was then purified directly by preparative HPLC (Waters,Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mmcolumn, 5-95% acetonitrile in water) to afford((R)-1-(4-fluorophenyl)-6-((6-((R)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanoneas a white solid (17 mg). LCMS (Method F, ES-API): RT 2.39 min,m+H=609.2; 1H NMR (400 MHz, CDCl₃): δ 8.46 (1H, d, J=2.6 Hz), 7.95 (1H,d, J=3.1 Hz), 7.64 (1H, dd, J=9.0, 2.4 Hz), 7.61 (1H, d, J=3.1 Hz),7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.3Hz), 6.27 (1H, d, J=9.1 Hz), 5.48-5.35 (2H, m), 4.17 (1H, d, J=16.8 Hz),3.92-3.59 (6H, m), 2.92-2.82 (2H, m), 2.77 (1H, d, J=12.3 Hz), 2.59-2.42(3H, m).

Example 10.(R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of pyrrolidine (0.065 mL, 0.783 mmol) and(R)-(1-(4-fluorophenyl)-6-(4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(183 mg, 0.261 mmol) in N-methylpyrrolidine (2 mL) was stirred in asealed vial at 100° C. for 22 hours. The cooled reaction mixture wasthen purified directly by preparative HPLC (Waters, Acidic (0.1% Formicacid), Waters X-Select Prep-C18, 5 μm 19×50 mm column, 5-95%acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin−1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanoneas an off-white solid (52 mg). LCMS (Method F, ES-API): RT 2.78 min,m+H=584.3; 1H NMR (400 MHz, CDCl₃): δ 8.63-8.62 (1H, m), 7.89 (1H, dt,J=8.0, 1.2 Hz), 7.81 (1H, td, J=7.5, 1.8 Hz), 7.51-7.47 (2H, m),7.46-7.41 (3H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 6.48-6.45 (3H, m),5.41 (1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.80-3.76 (1H,m), 3.33-3.30 (4H, m), 2.88 (1H, d, J=16.9 Hz), 2.85-2.76 (1H, m), 2.61(1H, d, J=12.1 Hz), 2.45-2.35 (2H, m), 2.07-2.01 (4H, m).

The following examples were similarly prepared from the appropriateintermediate:

Example 10A.(R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.56 min, m+H=532.8; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 8.36 (1H, d, J=2.8 Hz),8.25 (1H, d, J=1.7 Hz), 7.90-7.87 (1H, m), 7.83 (1H, dt, J=7.4, 1.7 Hz),7.49-7.41 (3H, m), 7.29-7.28 (2H, m), 7.19-7.13 (2H, m), 6.49 (1H, d,J=2.1 Hz), 5.52 (1H, dd, J=12.4, 2.1 Hz), 4.28 (1H, d, J=16.9 Hz),3.86-3.82 (1H, m), 3.25-3.23 (4H, m), 2.92-2.78 (3H, m), 2.59-2.48 (2H,m), 1.74-1.61 (6H, m).

Example 10B.(R)-(1-(4-fluorophenyl)-6-((5-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.42 min, m+H=585.3; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.7, 1.8, 0.9 Hz), 8.16 (1H, d, J=1.8 Hz),8.02 (1H, d, J=3.0 Hz), 7.89-7.86 (1H, m), 7.81 (1H, td, J=7.5, 1.8 Hz),7.48-7.40 (3H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.91 (1H, dd, J=2.6,2.1 Hz), 6.48 (1H, d, J=2.1 Hz), 5.50 (1H, dd, J=12.2, 2.1 Hz), 4.27(1H, d, J=17.0 Hz), 3.87-3.83 (1H, m), 3.32-3.26 (4H, m), 2.91-2.79 (3H,m), 2.59-2.49 (2H, m), 2.08-2.04 (4H, m).

Example 11.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(76 mg, 0.103 mmol) in 4 M HCl/dioxane (3 mL) was stirred at roomtemperature for 1 hour. The solvent was removed in vacuo (azeotropingtwice with toluene (˜4 mL)) to give a dark orange oil. This wasdissolved in dichloromethane (3 mL) and4-(trifluoromethyl)benzene-1-sulfonyl chloride (30.3 mg, 0.124 mmol) wasadded followed by diisopropylethylamine (90 μl, 0.516 mmol). Thereaction mixture was stirred at room temperature for 0.5 hour. Thesolvent was removed in vacuo to give a dark orange oil. The crudeproduct was purified by column chromatography on silica gel(gradient:0-40% ethyl acetate in isohexane) to afford(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanoneas a white solid (44 mg). LCMS (Method F, ES-API): RT 2.65 min,m+H=589.2; 1H NMR (400 MHz, CDCl₃): δ 8.86 (1H, d, J=2.1 Hz), 8.23 (1H,d, J=2.1 Hz), 7.84-7.82 (2H, m), 7.74-7.72 (2H, m), 7.45-7.40 (2H, m),7.28 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.48 (1H, dd,J=12.5, 2.1 Hz), 4.15 (1H, d, J=16.6 Hz), 3.92-3.87 (1H, m), 2.93-2.85(2H, m), 2.72 (1H, d, J=12.6 Hz), 2.56-2.49 (2H, m).

The following examples were similarly prepared from the appropriateintermediates:

Example 11A.(R)-(6-((4-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.74 min, m+H=548.9; 1H NMR (400 MHz,CDCl₃): δ 8.61 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.88-7.81 (2H, m),7.62-7.58 (2H, m), 7.51-7.37 (5H, m), 7.28 (1H, s), 7.20-7.12 (2H, m),6.49 (1H, d, J=2.1 Hz), 5.51 (1H, dd, J=12.2, 2.1 Hz), 4.28 (1H, d,J=16.9 Hz), 3.89-3.80 (1H, m), 2.92-2.77 (2H, m), 2.74 (1H, d, J=12.2Hz), 2.54-2.46 (2H, m).

Example 11B.(R)-(1-(4-fluorophenyl)-6-((4-methoxy-3-methylphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.69 min, m+H=559.0; 1H NMR (400 MHz,CDCl₃): δ 8.62 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.89-7.86 (1H, m),7.85-7.79 (1H, m), 7.52 (1H, dd, J=8.6, 2.1 Hz), 7.45-7.41 (4H, m), 7.28(1H, m), 7.19-7.12 (2H, m), 6.81 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=2.1Hz), 5.47 (1H, dd, J=12.1, 2.1 Hz), 4.30 (1H, d, J=17.0 Hz), 3.88-3.79(4H, m), 2.90-2.77 (2H, m), 2.67 (1H, d, J=12.1 Hz), 2.51-2.38 (2H, m),2.19 (3H, s).

Example 11C.(R)-(6-((3-chloro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.67 min, m+H=578.9; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.89-7.78 (2H, m), 7.67(1H, d, J=2.2 Hz), 7.57 (1H, dd, J=8.7, 2.2 Hz), 7.48-7.41 (3H, m), 7.28(1H, m), 7.18-7.13 (2H, m), 6.91 (1H, d, J=8.7 Hz), 6.48 (1H, d, J=2.1Hz), 5.50 (1H, dd, J=12.2, 2.1 Hz), 4.28 (1H, d, J=16.9 Hz), 3.94 (3H,m), 3.87-3.79 (1H, m), 2.91-2.78 (2H, m), 2.74 (1H, d, J=12.2 Hz),2.54-2.47 (2H, m).

Example 11D.(R)-(6-((3-fluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=563.2; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.90-7.87 (1H, m), 7.83(1H, dt, J=7.5, 1.7 Hz), 7.48-7.41 (4H, m), 7.37 (1H, dd, J=10.3, 2.3Hz), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.99-6.95 (1H, m), 6.48 (1H, d,J=2.1 Hz), 5.49 (1H, dd, J=12.1, 2.1 Hz), 4.29 (1H, d, J=16.9 Hz), 3.93(3H, s), 3.85-3.80 (1H, m), 2.91-2.77 (2H, m), 2.72 (1H, d, J=12.2 Hz),2.53-2.46 (2H, m).

Example 11E.(R)-(6-((2-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.67 min, m+H=547.2; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.7, 1.6, 1.0 Hz), 7.85-7.82 (1H, m), 7.80(1H, dt, J=7.3, 1.8 Hz), 7.59-7.55 (1H, m), 7.46-7.41 (3H, m), 7.28 (1H,s), 7.19-7.13 (2H, m), 6.95-6.90 (2H, m), 6.50 (1H, d, J=2.2 Hz), 5.57(1H, dd, J=12.8, 1.8 Hz), 4.29 (1H, d, J=16.9 Hz), 3.95-3.91 (1H, m),2.97 (1H, dd, 12.9, 1.1 Hz), 2.91-2.79 (2H, m), 2.74-2.68 (1H, m),2.51-2.47 (1H, m), 2.37 (3H, s).

Example 11F.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=535.1; 1H NMR (400 MHz,CDCl₃): δ 8.88 (1H, d, J=2.4 Hz), 8.25 (1H, d, J=2.4 Hz), 7.52-7.50 (2H,m), 7.45-7.40 (2H, m), 7.37-7.36 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H,m), 6.49 (1H, d, J=2.3 Hz), 5.45 (1H, dd, J=12.1, 2.3 Hz), 4.18 (1H, d,J=16.9 Hz), 3.87-3.83 (1H, m), 2.92-2.82 (2H, m), 2.63 (1H, d, J=12.4Hz), 2.50-2.39 (5H, m).

Example 11G.(R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS (Method F, ES-API): RT 2.48 min, m+H=540.0; 1H NMR (400 MHz,CDCl₃): δ 8.68-8.66 (1H, m), 7.93-7.78 (5H, m), 7.60 (1H, td, J=7.8, 0.6Hz), 7.50 (1H, ddd, J=6.8, 4.8, 2.2 Hz), 7.45-7.39 (2H, m), 7.28 (1H,m), 7.19-7.13 (2H, m), 6.50 (1H, d, J=2.1 Hz), 5.60 (1H, dd, J=12.4, 2.1Hz), 4.26 (1H, d, J=16.9 Hz), 3.92-3.83 (1H, m), 2.90-2.78 (3H, m),2.58-2.49 (2H, m).

Example 11H.(R)-(6-((4-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.62 min, m+H=581.2; 1H NMR (400 MHz,CDCl₃): δ 8.62 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.89-7.87 (1H, m), 7.83(1H, dt, J=7.5, 1.7 Hz), 7.71-7.68 (2H, m), 7.49-7.40 (3H, m), 7.28 (1H,s), 7.19-7.13 (4H, m), 6.57 (1H, t, J=72.4 Hz), 6.48 (1H, d, J=2.3 Hz),5.52 (1H, dd, J=12.2, 2.1 Hz), 4.28 (1H, d, J=16.9 Hz), 3.86-3.82 (1H,m), 2.90-2.78 (2H, m), 2.74 (1H, d, J=12.2 Hz), 2.54-2.46 (2H, m).

Example 11I.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.79 min, m+H=599.2; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.91-7.88 (1H, m), 7.84(1H, dt, J=7.5, 1.7 Hz), 7.64-7.62 (1H, m), 7.54-7.47 (3H, m), 7.45-7.38(3H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.49 (1H, d, J=2.3 Hz), 5.55(1H, dd, J=12.4, 2.2 Hz), 4.29 (1H, d, J=16.9 Hz), 3.86-3.81 (1H, m),2.91-2.74 (3H, m), 2.54-2.47 (2H, m).

Example 11J.(R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.67 min, m+H=551.2; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 7.88 (1H, ddd, J=7.9, 1.5,1.0 Hz), 7.84 (1H, dt, J=7.3, 1.7 Hz), 7.48 (1H, ddd, J=7.4, 4.7, 1.5Hz), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.22-7.13 (4H, m), 6.98 (1H, tt,J=8.5, 2.3 Hz), 6.49 (1H, d, J=2.1 Hz), 5.56 (1H, dd, J=12.3, 2.1 Hz),4.28 (1H, d, J=16.9 Hz), 3.87-3.82 (1H, m), 2.92-2.78 (3H, m), 2.62-2.55(1H, m), 2.53-2.48 (1H, m).

Example 11K.(R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.56 min, m+H=535.0; 1H NMR (400 MHz,CDCl₃): δ 8.86 (1H, d, J=2.2 Hz), 8.24 (1H, d, J=2.2 Hz), 7.59-7.55 (2H,m), 7.47-7.39 (2H, m), 7.27-7.25 (3H, m), 7.19-7.12 (2H, m), 6.49 (1H,d, J=2.0 Hz), 5.43 (1H, dd, J=12.3, 2.0 Hz), 4.17 (1H, d, J=16.9 Hz),3.84 (1H, ddt, J=8.5, 4.4, 2.0 Hz), 2.91-2.80 (2H, m), 2.61 (1H, d,J=12.3 Hz), 2.49-2.37 (5H, m).

Example 11L.(R)-(6-((3-(difluoromethoxy)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.63 min, m+H=581.2; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.89-7.87 (1H, m), 7.83(1H, dt, J=7.5, 1.7 Hz), 7.56-7.53 (1H, m), 7.49-7.40 (5H, m), 7.31-7.28(2H, m), 7.19-7.13 (2H, m), 6.55 (1H, t, J=72.7 Hz), 6.48 (1H, d, J=2.3Hz), 5.52 (1H, dd, J=12.2, 2.1 Hz), 4.28 (1H, d, J=16.9 Hz), 3.86-3.81(1H, m), 2.90-2.75 (3H, m), 2.55-2.46 (2H, m).

Example 11M.(R)-(6-((3,4-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.76 min, m+H=543.0; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.92-7.80 (2H, m),7.49-7.39 (5H, m), 7.28 (1H, s), 7.20-7.13 (3H, m), 6.46 (1H, d, J=2.1Hz), 5.47 (1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d, J=17.0 Hz), 3.83-3.79(1H, m), 2.91-2.71 (2H, m), 2.67 (1H, d, J=12.2 Hz), 2.50-2.38 (2H, m),2.28 (6H, s).

Example 11N.(R)-(6-((3,5-dimethylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.78 min, m+H=543.0; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.90-7.88 (1H, m), 7.83(1H, dt, J=7.5, 1.7 Hz), 7.49-7.40 (3H, m), 7.28 (3H, m), 7.19-7.13 (3H,m), 6.47 (1H, d, J=2.3 Hz), 5.48 (1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d,J=16.9 Hz), 3.83-3.79 (1H, m), 2.90 (1H, d, J=16.9 Hz), 2.87-2.78 (1H,m), 2.70 (1H, d, J=12.3 Hz), 2.50-2.42 (2H, m), 2.34 (6H, m).

Example 11O.(R)-(1-(4-fluorophenyl)-6-((6-methylpyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.46 min, m+H=530.1; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.6, 1.0 Hz), 7.85-7.78 (2H, m),7.69-7.65 (1H, m), 7.59-7.57 (1H, m), 7.48-7.42 (3H, m), 7.29 (1H, s),7.27-7.25 (1H, m), 7.19-7.13 (2H, m), 6.51 (1H, d, J=1.4 Hz), 5.62 (1H,dd, J=12.9, 2.0 Hz), 4.31 (1H, d, J=16.9 Hz), 4.00-3.96 (1H, m), 3.19(1H, d, J=13.0 Hz), 2.95-2.91 (3H, m), 2.59 (3H, s), 2.50-2.46 (1H, m).

Example 11P.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.65 min, m+H=551.1; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.8, 1.7, 1.0 Hz), 7.88 (1H, ddd, J=7.9, 1.7,1.0 Hz), 7.84 (1H, dt, J=7.3, 1.7 Hz), 7.52-7.40 (5H, m), 7.28 (1H, s),7.24-7.22 (1H, m), 7.20-7.13 (2H, m), 6.49 (1H, d, J=2.1 Hz), 5.53 (1H,dd, J=12.2, 2.0 Hz), 4.28 (1H, d, J=16.9 Hz), 3.88-3.83 (1H, m),2.91-2.78 (3H, m), 2.59-2.48 (2H, m).

Example 11Q.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.72 min, m+H=569.1; 1H NMR (400 MHz,CDCl₃): δ 8.63 (1H, ddd, J=4.7, 1.5, 1.1 Hz), 7.89-7.83 (2H, m), 7.49(1H, ddd, J=6.6, 4.7, 1.7 Hz), 7.46-7.41 (2H, m), 7.34-7.31 (2H, m),7.28 (1H, s), 7.20-7.14 (2H, m), 6.50 (1H, d, J=2.1 Hz), 5.55 (1H, dd,J=12.2, 2.0 Hz), 4.26 (1H, d, J=16.9 Hz), 3.89-3.84 (1H, m), 2.91-2.79(3H, m), 2.66-2.60 (1H, m), 2.54-2.51 (1H, m).

Example 11R.(R)-(6-((3-chloro-4-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.75 min, m+H=567.0; 1H NMR (400 MHz,CDCl₃): δ 8.61 (1H, dt, J=4.7, 1.3 Hz), 7.86-7.79 (2H, m), 7.73 (1H, dd,J=6.7, 2.3 Hz), 7.57 (1H, ddd, J=8.6, 4.3, 2.3 Hz), 7.47-7.40 (3H, m),7.27 (1H, s), 7.18-7.13 (3H, m), 6.48 (1H, d, J=2.0 Hz), 5.50 (1H, br.dd, J=12.5, 1.4 Hz), 4.24 (1H, d, J=16.9 Hz), 3.86 (1H, dtd, J=8.5, 3.9,1.9 Hz), 2.91-2.79 (3H, m), 2.61 (1H, td, J=11.6, 3.4 Hz), 2.55-2.46(1H, m).

Example 11S.(R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS (Method F, ES-API): RT 2.57 min, m+H=554.0; 1H NMR (400 MHz,CDCl₃): δ 8.50 (1H, br. d, J=4.9 Hz), 7.93-7.91 (2H, m), 7.79 (1H, dt,J=7.8, 1.3 Hz), 7.69-7.68 (1H, m), 7.63-7.58 (1H, m), 7.44-7.41 (2H, m),7.30 (1H, ddd, J=4.9, 1.7, 0.7 Hz), 7.27 (1H, s), 7.19-7.13 (2H, m),6.49 (1H, d, J=2.0 Hz), 5.64 (1H, dd, J=12.4, 2.0 Hz), 4.25 (1H, d,J=16.9 Hz), 3.89 (1H, ddt, J=8.5, 3.9, 2.0 Hz), 2.85-2.79 (3H, m),2.63-2.50 (2H, m), 2.41 (3H, s).

Example 11T.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.25 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, dd, J=5.0, 0.5 Hz), 7.71 (1H, m), 7.67-7.65 (2H, m),7.46-7.41 (2H, m), 7.29-7.26 (2H, m), 7.19-7.13 (2H, m), 6.48 (1H, d,J=2.1 Hz), 5.47 (1H, dd, J=12.1, 2.1 Hz), 4.29 (1H, d, J=16.9 Hz), 3.91(3H, s), 3.80-3.75 (1H, m), 2.92-2.78 (2H, m), 2.68 (1H, d, J=12.0 Hz),2.50-2.42 (2H, m), 2.40 (3H, s).

Example 11U.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.74 min, m+H=565.2; 1H NMR (400 MHz,CDCl₃): δ 8.46 (1H, dd, J=5.0, 0.5 Hz), 7.68 (1H, m), 7.50-7.40 (4H, m),7.29-7.26 (2H, m), 7.24-7.13 (3H, m), 6.48 (1H, d, J=2.1 Hz), 5.55 (1H,dd, J=12.4, 2.1 Hz), 4.27 (1H, d, J=16.9 Hz), 3.89-3.84 (1H, m),2.88-2.78 (3H, m), 2.62-2.56 (1H, m), 2.53-2.48 (1H, m), 2.40 (3H, s).

Example 11V.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.13 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.50 (1H, dd, J=4.8, 0.5 Hz), 7.71-7.70 (1H, m), 7.47-7.42(3H, m), 7.35 (1H, d, J=1.4 Hz), 7.29 (1H, s), 7.26-7.25 (1H, m),7.19-7.13 (2H, m), 6.48 (1H, d, J=2.1 Hz), 5.56 (1H, dd, J=12.5, 2.1Hz), 4.32 (1H, d, J=16.9 Hz), 3.90-3.85 (1H, m), 3.72 (3H, s), 2.96 (1H,d, J=12.5 Hz), 2.91 (1H, d, J=16.9 Hz), 2.87-2.78 (1H, m), 2.74-2.68(1H, m), 2.49-2.44 (1H, m), 2.39 (3H, s).

Example 11W.(R)-(6-((3,5-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.76 min, m+H=565.0; 1H NMR (400 MHz,CDCl₃): δ 8.51 (1H, br. d, J=4.9 Hz), 7.72-7.69 (1H, m), 7.46-7.41 (2H,m), 7.32-7.27 (2H, m), 7.20-7.13 (4H, m), 6.97 (1H, tt, J=8.5, 2.3 Hz),6.49 (1H, d, J=2.1 Hz), 5.61 (1H, dd, J=12.3, 2.1 Hz), 4.29 (1H, d,J=16.9 Hz), 3.85 (1H, ddt, J=8.4, 3.9, 2.1 Hz), 2.90-2.77 (3H, m),2.63-2.57 (1H, m), 2.50 (1H, br. dt, J=14.9, 2.0 Hz), 2.41 (3H, s).

Example 11X.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.82 min, m+H=583.0; 1H NMR (400 MHz,CDCl₃): δ 8.48-8.47 (1H, m), 7.69-7.68 (1H, m), 7.47-7.39 (2H, m),7.36-7.29 (3H, m), 7.27 (1H, s), 7.20-7.13 (2H, m), 6.50 (1H, d, J=2.1Hz), 5.58 (1H, dd, J=12.5, 2.1 Hz), 4.26 (1H, d, J=16.9 Hz), 3.88 (1H,dtd, J=7.9, 4.0, 2.1 Hz), 2.91-2.76 (3H, m), 2.72-2.62 (1H, m),2.56-2.50 (1H, m), 2.41 (3H, s).

Example 11Y.(R)-(1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.32 min, m+H=593.2; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.8 Hz), 8.27-8.26 (1H, m), 8.09(1H, ddd, J=7.9, 1.7, 1.2 Hz), 7.96 (1H, ddd, J=7.9, 1.7, 1.2 Hz),7.87-7.80 (2H, m), 7.70-7.66 (1H, m), 7.48 (1H, ddd, J=6.6, 4.7, 1.7Hz), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.48 (1H, d,J=2.1 Hz), 5.56 (1H, dd, J=12.3, 2.1 Hz), 4.23 (1H, d, J=16.9 Hz),3.91-3.87 (1H, m), 3.08 (3H, s), 2.91-2.79 (3H, m), 2.62-2.48 (2H, m).

Example 11Z.(R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoicacid

LCMS (Method F, ES-API): RT 2.38 min, m+H=559.

Example 11AA.(R)-(1-(4-fluorophenyl)-6-((3-(methoxymethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.54 min, m+H=559.3; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.7, 1.4, 0.8 Hz), 7.91-7-89 (1H, m), 7.83(1H, dt, J=7.5, 1.5 Hz), 7.65 (1H, m), 7.62-7.59 (1H, m), 7.54-7.52 (1H,m), 7.49-7.40 (4H, m), 7.29 (1H, s), 7.18-7.13 (2H, m), 6.46 (1H, d,J=2.1 Hz), 5.50 (1H, dd, J=12.4, 2.1 Hz), 4.48 (2H, s), 4.30 (1H, d,J=16.9 Hz), 3.84-3.79 (1H, m), 3.42 (3H, s), 2.91-2.77 (2H, m), 2.69(1H, d, J=12.1 Hz), 2.47-2.41 (2H, m).

Example 11AB.(R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-211-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.40 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.65 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 8.06 (1H, d, J=2.1 Hz),7.89 (1H, dt, J=7.8, 1.2 Hz), 7.82 (1H, td, J=7.8, 1.8 Hz), 7.47-7.41(3H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 7.04 (1H, d, J=2.1 Hz), 6.48(1H, d, J=2.1 Hz), 5.47 (1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d, J=17.0Hz), 4.25-4.20 (2H, m), 3.82-3.77 (1H, m), 3.54-3.52 (2H, m), 3.19 (3H,s), 2.90 (1H, d, J=11.5 Hz), 2.85-2.75 (1H, m), 2.70 (1H, d, J=12.2 Hz),2.52-2.45 (2H, m).

Example 11AC.(R)-(1-(4-fluorophenyl)-6-((2,3,4-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.69 min, m+H=569.0; 1H NMR (400 MHz,CDCl₃): δ 8.62-8.59 (1H, m), 7.86-7.78 (2H, m), 7.49-7.40 (4H, m), 7.27(1H, s), 7.19-7.13 (2H, m), 6.97-6.91 (1H, m), 6.52 (1H, s), 5.57 (1H,dd, J=12.8, 1.8 Hz), 4.24 (1H, d, J=16.9 Hz), 4.02-3.95 (1H, m), 3.09(1H, d, J=12.3 Hz), 2.87-2.80 (3H, m), 2.57-2.49 (1H, m).

Example 11AD.(R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.66 min, m+H=584.2; 1H NMR (400 MHz,CDCl₃): δ 8.66-8.64 (1H, m), 8.07-8.03 (1H, m), 7.97 (1H, d, J=7.6 Hz),7.85-7.79 (3H, m), 7.48-7.43 (3H, m), 7.30 (1H, s), 7.21-7.15 (2H, m),6.54 (1H, d, J=2.1 Hz), 5.64 (1H, dd, J=13.2, 2.0 Hz), 4.30 (1H, d,J=16.9 Hz), 4.06-4.01 (1H, m), 3.32 (1H, d, J=13.0 Hz), 3.07 (1H, dd,J=12.6, 3.5 Hz), 2.91 (1H, d, J=16.9 Hz), 2.89-2.80 (1H, m), 2.54-2.50(1H, m).

Example 11AE.(R)-(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.77 min, m+H=598.2; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, d, J=4.9 Hz), 8.07-8.03 (1H, m), 7.98 (1H, d, J=7.7Hz), 7.82 (1H, dd, 7.7, 1.1 Hz), 7.65 (1H, s), 7.48-7.43 (2H, m), 7.29(1H, s), 7.27-7.26 (1H, m), 7.20-7.14 (2H, m), 6.53 (1H, d, J=2.0 Hz),5.67 (1H, dd, J=12.8, 1.7 Hz), 4.29 (1H, d, J=16.9 Hz), 4.06-4.02 (1H,m), 3.31 (1H, d, J=13.0 Hz), 3.08 (1H, dd, J=12.6, 3.5 Hz), 2.92-2.80(2H, m), 2.55-2.50 (1H, m), 2.39 (3H, s).

Example 11AF.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.88 min, m+H=582.9; 1H NMR (400 MHz,CDCl₃): δ 8.61 (1H, ddd, J=4.7, 1.7, 1.0 Hz), 7.89-7.81 (2H, m), 7.74(1H, dd, J=1.7, 0.5 Hz), 7.49-7.38 (5H, m), 7.28 (1H, s), 7.20-7.12 (2H,m), 6.50 (1H, d, J=2.0 Hz), 5.54 (1H, dd, J=12.4, 2.0 Hz), 4.26 (1H, d,J=16.9 Hz), 3.88 (1H, ddt, J=8.4, 3.9, 2.0 Hz), 2.93-2.79 (3H, m),2.65-2.50 (2H, m).

Example 11AG.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.83 min, m+H=597.0; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, dd, J=4.9, 0.38 Hz), 8.00-7.88 (2H, m), 7.80-7.78(1H, m), 7.71-7.68 (1H, m), 7.61 (1H, t, J=7.8 Hz), 7.46-7.39 (2H, m),7.29-7.27 (2H, m), 7.19-7.13 (2H, m), 6.48 (1H, d, J=2.0 Hz), 5.61 (1H,dd, J=12.3, 2.0 Hz), 4.27 (1H, d, J=16.9 Hz), 3.91-3.81 (1H, m),2.92-2.78 (3H, m), 2.62-2.49 (2H, m), 2.40 (3H, s).

Example 11AH.(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.39 min, m+H=547.0; 1H NMR (400 MHz,CDCl₃): δ 8.51 (1H, d, J=4.9 Hz), 7.71 (2H, s), 7.66 (1H, d, J=0.6 Hz),7.47-7.40 (2H, m), 7.30-7.27 (2H, m), 7.20-7.13 (2H, m), 6.48 (1H, d,J=2.0 Hz), 5.49 (1H, dd, J=12.0, 2.0 Hz), 4.30 (1H, d, J=16.9 Hz), 4.17(2H, q, J=7.3 Hz), 3.82-3.71 (1H, m), 2.94-2.79 (2H, m), 2.69 (1H, d,J=12.0 Hz), 2.52-2.41 (2H, m), 2.40 (3H, s), 1.50 (3H, t, J=7.3 Hz).

Example 11AI.(R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.33 min, m+H=547.0; 1H NMR (400 MHz,CDCl₃): δ 8.46 (1H, d, J=4.9 Hz), 7.71-7.68 (1H, m), 7.61 (1H, s),7.46-7.41 (2H, m), 7.27-7.25 (2H, m), 7.20-7.13 (2H, m), 6.49 (1H, d,J=2.0 Hz), 5.52 (1H, dd, J=12.1, 2.0 Hz), 4.24 (1H, d, J=16.9 Hz),3.84-3.80 (1H, m), 3.69 (3H, m), 2.90-2.77 (3H, m), 2.61-2.48 (2H, m),2.40 (3H, s), 2.34 (3H, s).

Example 11AJ.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.49 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.43 (1H, d, J=5.0 Hz), 7.68 (1H, m), 7.47-7.41 (2H, m), 7.32(1H, d, J=2.0 Hz), 7.27-7.25 (2H, m), 7.20-7.14 (2H, m), 6.64 (1H, d,J=2.0 Hz), 6.52 (1H, br s), 5.59 (1H, dd, J=12.4, 2.2 Hz), 4.27 (1H, d,J=16.9 Hz), 3.92-3.89 (4H, m), 3.03 (1H, d, J=12.5 Hz), 2.90-2.76 (3H,m), 2.59-2.55 (1H, m), 2.40 (3H, s).

Example 11AK.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.36 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.51 (1H, dd, J=5.0, 0.5 Hz), 7.71 (1H, m), 7.47-7.42 (2H, m),7.38 (1H, d, J=2.2 Hz), 7.30 (1H, s), 7.27-7.25 (1H, m), 7.19-7.13 (2H,m), 6.58 (1H, d, J=2.2 Hz), 6.49 (1H, d, J=2.1 Hz), 5.55 (1H, dd,J=12.4, 2.0 Hz), 4.33 (1H, d, J=16.9 Hz), 3.95 (3H, s), 3.88-3.83 (1H,m), 2.92 (1H, d, J=16.9 Hz), 2.91 (1H, d, J=12.4 Hz), 2.88-2.79 (1H, m),2.68-2.61 (1H, m), 2.49-2.44 (1H, m), 2.39 (3H, s).

Example 11AL.(R)-(6-((4-fluoro-3-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.90 min, m+H=561.2; 1H NMR (400 MHz,CDCl₃): δ 8.50 (1H, dd, J=5.0, 0.4 Hz), 7.69-7.68 (1H, m), 7.53-7.49(2H, m), 7.45-7.40 (2H, m), 7.28-7.26 (2H, m), 7.19-7.13 (2H, m),7.05-7.00 (1H, m), 6.47 (1H, d, J=2.1 Hz), 5.52 (1H, dd, J=12.4, 2.3Hz), 4.28 (1H, d, J=16.9 Hz), 3.86-3.81 (1H, m), 2.89-2.78 (2H, m), 2.74(1H, d, J=12.3 Hz), 2.54-2.46 (2H, m), 2.40 (3H, s), 2.28 (3H, d, J=1.7Hz).

Example 11AM.(R)-(1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.58 min, m+H=601.3; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, d, J=4.9 Hz), 8.06 (1H, d, J=2.0 Hz), 7.71 (1H, m),7.46-7.41 (2H, m), 7.28 (1H, s), 7.25 (1H, m), 7.19-7.12 (2H, m), 7.04(1H, d, J=2.0 Hz), 6.46 (1H, d, J=2.1 Hz), 5.50 (1H, dd, J=12.3, 2.1Hz), 4.29 (1H, d, J=16.9 Hz), 4.22-4.20 (2H, m), 3.80-3.76 (1H, m),3.54-3.52 (2H, m), 3.19 (3H, s), 2.88 (1H, d, J=16.9 Hz), 2.84-2.75 (1H,m), 2.69 (1H, d, J=12.3 Hz), 2.52-2.44 (2H, m), 2.40 (3H, s).

Example 11AN.(R)-(6-((2,3-dihydrobenzofuran-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.73 min, m+H=571.2; 1H NMR (400 MHz,CDCl₃): δ 8.47 (1H, d, J=4.9 Hz), 7.71-7.70 (1H, m), 7.49-7.41 (4H, m),7.27-7.26 (2H, m), 7.19-7.13 (2H, m), 6.78-6.75 (1H, m), 6.47 (1H, d,J=2.0 Hz), 5.51 (1H, dd, J=12.3, 2.1 Hz), 4.67-4.63 (2H, m), 4.30 (1H,d, J=16.9 Hz), 3.84-3.79 (1H, m), 3.24-3.20 (2H, m), 2.90-2.78 (2H, m),2.67 (1H, d, J=12.3 Hz), 2.48-2.40 (5H, m).

Example 11AO.(R)-5-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylindolin-2-one

LCMS (Method F, ES-API): RT 2.44 min, m+H=598.3; 1H NMR (400 MHz,CDCl₃): δ 8.44 (1H, d, J=4.9 Hz), 7.70-7.68 (2H, m), 7.52 (1H, d, J=0.9Hz), 7.45-7.40 (2H, m), 7.26 (1H, s), 7.24-7.23 (1H, m), 7.19-7.13 (2H,m), 6.82 (1H, d, J=8.3 Hz), 6.47 (1H, d, J=2.0 Hz), 5.53 (1H, dd,J=12.3, 2.0 Hz), 4.25 (1H, d, J=16.9 Hz), 3.88-3.84 (1H, m), 3.53, 3.47(2H, AB system, J=22.4 Hz), 3.22 (3H, s), 2.89-2.79 (2H, m), 2.72 (1H,d, J=12.3 Hz), 2.53-2.46 (2H, m), 2.39 (3H, s).

Example 11AP.(R)-(1-(4-fluorophenyl)-6-((3-(methylsulfonyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.52 min, m+H=607.2; 1H NMR (400 MHz,CDCl₃): δ 8.49 (1H, d, J=4.9 Hz), 8.26-8.25 (1H, m), 8.09 (1H, ddd,J=7.9, 1.7, 1.2 Hz), 7.97 (1H, ddd, J=7.9, 1.7, 1.2 Hz), 7.69-7.66 (1H,m), 7.45-7.40 (2H, m), 7.29-7.26 (2H, m), 7.19-7.13 (2H, m), 6.48 (1H,d, J=2.1 Hz), 5.60 (1H, dd, J=12.3, 2.1 Hz), 4.23 (1H, d, J=16.9 Hz),3.92-3.87 (1H, m), 3.08 (3H, s), 2.88-2.79 (3H, m), 2.63-2.49 (2H, m),2.40 (3H, s).

Example 11AQ.(R)-(6-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.33 min, m+H=547.0; 1H NMR (400 MHz,CDCl₃): δ 8.44 (1H, d, J=4.9 Hz), 7.71-7.69 (1H, m), 7.59 (1H, m),7.46-7.41 (2H, m), 7.28-7.26 (2H, m), 7.20-7.13 (2H, m), 6.50 (1H, d,J=2.0 Hz), 5.49 (1H, dd, J=12.1, 2.0 Hz), 4.28 (1H, d, J=16.9 Hz),3.85-3.76 (4H, m), 2.92-2.78 (3H, m), 2.63-2.48 (2H, m), 2.40 (3H, s),2.27 (3H, s).

Example 11AR.(R)-(6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.60 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.50 (1H, d, J=4.9 Hz), 7.71 (1H, s), 7.45-7.41 (2H, m),7.28-7.26 (2H, m), 7.22-7.13 (4H, m), 6.89 (1H, d, J=8.5 Hz), 6.46 (1H,d, J=1.9 Hz), 5.49 (1H, dd, J=12.2, 1.9 Hz), 4.31-4.25 (5H, m),3.81-3.73 (1H, m), 2.92-2.77 (2H, m), 2.68 (1H, d, J=12.2 Hz), 2.50-2.39(5H, m).

Example 11AS.(R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 3.03 min, m+H=615.2; 1H NMR (400 MHz,CDCl₃): δ 8.47 (1H, dd, J=4.9, 0.3 Hz), 7.69-7.65 (2H, m), 7.58-7.56(1H, m), 7.48 (1H, br d, J=9.4 Hz), 7.45-7.40 (2H, m), 7.28 (1H, ddd,J=4.9, 1.6, 0.7 Hz), 7.26 (1H, s), 7.19-7.13 (2H, m), 6.49 (1H, d, J=2.0Hz), 5.64 (1H, dd, J=12.5, 2.0 Hz), 4.23 (1H, d, J=16.9 Hz), 3.92-3.88(1H, m), 2.91-2.80 (3H, m), 2.69-2.63 (1H, m), 2.55-2.50 (1H, m), 2.39(3H, s).

Example 11AT.(R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.93 min, m+H=601.2; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.9, 1.5, 1.1 Hz), 7.87-7.81 (2H, m),7.71-7.67 (1H, m), 7.57 (1H, br d, J=8.2 Hz), 7.51-7.47 (2H, m),7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.50 (1H, d, J=2.0Hz), 5.59 (1H, dd, J=12.4, 2.0 Hz), 4.25 (1H, d, J=16.9 Hz), 3.92-3.87(1H, m), 2.91-2.80 (3H, m), 2.67-2.61 (1H, m), 2.55-2.51 (1H, m).

Example 11AU.(R)-34(4a-(4-ethylpicolinoyl)-1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS (Method F, ES-API): RT 2.79 min, m+H=568.2; 1H NMR (400 MHz,CDCl₃): δ 8.53 (1H, dd, J=4.9, 0.5 Hz), 7.95 (1H, m), 7.91 (1H, ddd,J=7.9, 1.9, 1.2 Hz), 7.78 (1H, ddd, J=7.9, 1.2, 0.3 Hz), 7.71-7.70 (1H,m), 7.59 (1H, dt, J=7.9, 0.5 Hz), 7.45-7.40 (2H, m), 7.33-7.32 (1H, m),7.27 (1H, s), 7.19-7.13 (2H, m), 6.49 (1H, d, J=2.0 Hz), 5.64 (1H, dd,J=12.3, 2.0 Hz), 4.25 (1H, d, J=16.9 Hz), 3.91-3.86 (1H, m), 2.88-2.80(3H, m), 2.71 (2H, q, J=7.7 Hz), 2.63-2.50 (2H, m), 1.27 (3H, t, J=7.7Hz).

Example 11AV.(R)-(4-ethylpyridin-2-yl)(1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone

LCMS (Method F, ES-API): RT 2.93 min, m+H=612.2; 1H NMR (400 MHz,CDCl₃): δ 8.51 (1H, dd, J=4.9, 0.5 Hz), 8.06-8.02 (1H, m), 7.99-7.97(1H, m), 7.81 (1H, dd, J=7.9, 1.2 Hz), 7.67 (1H, m), 7.48-7.43 (2H, m),7.29 (1H, s), 7.28-7.27 (1H, m), 7.20-7.14 (2H, m), 6.53 (1H, d, J=2.0Hz), 5.67 (1H, dd, J=12.3, 2.0 Hz), 4.28 (1H, d, J=16.9 Hz), 4.06-4.02(1H, m), 3.31 (1H, d, J=13.0 Hz), 3.12-3.05 (1H, m), 2.91-2.81 (2H, m),2.69 (2H, q, J=7.7 Hz), 2.54-2.50 (1H, m), 1.26 (3H, t, J=7.7 Hz).

Example 11AW.(R)-3-((1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoicacid

LCMS (Method F, ES-API): RT 2.47 min, m+H=573.0; 1H NMR (400 MHz,CDCl₃): δ 8.55 (1H, d, J=5.0 Hz), 8.17 (1H, dt, J=7.9, 1.2 Hz), 8.07(1H, t, J=1.7 Hz), 7.88 (1H, dt, J=8.2, 1.2 Hz), 7.70 (1H, t, J=7.9 Hz),7.60 (1H, m), 7.51-7.45 (3H, m), 7.41-7.35 (3H, m), 6.63 (1H, s), 5.39(1H, d, J=12.2 Hz), 4.13 (1H, d, J=17.0 Hz), 3.77-3.71 (1H, m),2.92-2.84 (2H, m), 2.69-2.44 (3H, m), 2.38 (3H, s).

Example 11AX.(R)-(6-((3,5-dimethylisoxazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.79 min, m+H=548.2; 1H NMR (400 MHz,CDCl₃): δ 8.38 (1H, d, J=4.9 Hz), 7.65-7.64 (1H, m), 7.46-7.41 (2H, m),7.28-7.26 (1H, m), 7.25 (1H, s), 7.20-7.14 (2H, m), 6.52 (1H, s), 5.49(1H, dd, J=12.6, 2.1 Hz), 4.24 (1H, d, J=16.9 Hz), 3.95-3.92 (1H, m),3.04 (1H, d, J=12.6 Hz), 2.90-2.79 (3H, m), 2.62-2.55 (1H, m), 2.53 (3H,s), 2.39 (3H, s), 2.21 (3H, s).

Example 11AY.(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.28 min, m+H=533.0; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.92-7.87 (1H, m), 7.83(1H, td, J=7.5, 1.7 Hz), 7.71 (1H, s), 7.66 (1H, s), 7.48-7.41 (3H, m),7.30 (1H, s), 7.21-7.13 (2H, m), 6.49 (1H, d, J=2.0 Hz), 5.46 (1H, dd,J=12.0, 2.0 Hz), 4.31 (1H, d, J=16.9 Hz), 4.17 (2H, q, J=7.3 Hz),3.80-3.75 (1H, m), 2.95-2.77 (2H, m), 2.69 (1H, d, J=12.0 Hz), 2.52-2.40(2H, m), 1.50 (3H, t, J=7.3 Hz).

Example 11AZ.(R)-(1-phenyl-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.72 min, m+H=565.0; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.94-7.78 (5H, m), 7.61(1H, t, J=7.8 Hz), 7.50-7.45 (5H, m), 7.39-7.33 (1H, m), 7.29 (1H, s),6.56 (1H, d, J=2.1 Hz), 5.56 (1H, dd, J=12.3, 2.1 Hz), 4.25 (1H, d,J=16.9 Hz), 3.90-3.84 (1H, m), 2.92-2.78 (3H, m), 2.58-2.48 (2H, m).

Example 11BA.(R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.54 min, m+H=547.1; 1H NMR (400 MHz,CDCl₃): δ 8.42 (1H, d, J=4.9 Hz), 7.70-7.68 (1H, m), 7.48-7.41 (2H, m),7.26-7.24 (2H, m), 7.21-7.14 (2H, m), 6.52 (1H, d, J=1.9 Hz), 6.40 (1H,d, J=0.39 Hz), 5.58 (1H, dd, J=12.5, 1.9 Hz), 4.28 (1H, d, J=16.8 Hz),3.94-3.87 (1H, m), 3.84 (3H, s), 3.02 (1H, d, J=12.5 Hz), 2.91-2.75 (3H,m), 2.60-2.53 (1H, m), 2.39 (3H, s), 2.17 (3H, s).

Example 11BB.(R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.99 min, m+H=598.2; 1H NMR (400 MHz,CDCl₃): δ 8.83 (1H, d, J=5.0 Hz), 8.46 (1H, dd, J=5.0, 0.4 Hz), 7.86(1H, m), 7.71 (1H, dd, J=5.0, 1.3 Hz), 7.63-7.62 (1H, m), 7.45-7.40 (2H,m), 7.29-7.26 (2H, m), 7.19-7.13 (2H, m), 6.50 (1H, d, J=2.0 Hz), 5.64(1H, dd, J=12.6, 2.0 Hz), 4.20 (1H, d, J=16.9 Hz), 3.95-3.90 (1H, m),2.97 (1H, d, J=12.6 Hz), 2.88-2.80 (2H, m), 2.77-2.70 (1H, m), 2.57-2.53(1H, m), 2.39 (3H, s).

Example 11BC.(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 3.13 min, m+H=598.2; 1H NMR (400 MHz,CDCl₃): δ 8.82 (1H, d, J=4.9 Hz), 8.50 (1H, dd, J=4.9, 0.9 Hz), 7.98(1H, m), 7.65-7.62 (2H, m), 7.47-7.42 (2H, m), 7.27-7.26 (2H, m),7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.78 (1H, dd, J=12.9, 2.0Hz), 4.25 (1H, d, J=16.9 Hz), 4.07-4.02 (1H, m), 3.28 (1H, d, J=12.9Hz), 3.02-2.96 (1H, m), 2.92-2.83 (2H, m), 2.54-2.49 (1H, m), 2.38 (3H,s).

Example 11BD.(R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.54 min, m+H=533.2; 1H NMR (400 MHz,CDCl₃): δ 8.45 (1H, d, J=4.9 Hz), 7.74 (1H, s), 7.71-7.70 (1H, m),7.46-7.41 (2H, m), 7.28 (1H, s) 7.26-7.25 (2H, m), 7.20-7.14 (2H, m),6.49 (1H, d, J=2.0 Hz), 5.52 (1H, dd, J=12.0, 2.0 Hz), 4.27 (1H, d,J=16.9 Hz), 3.84-3.81 (1H, m), 2.91-2.78 (3H, m), 2.60-2.49 (2H, m),2.39 (6H, s).

Example 11BE.(R)-(1-(4-fluorophenyl)-6-((2-(trifluoromethyl)pyridin-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 3.07 min, m+H=584.2; 1H NMR (400 MHz,CDCl₃): δ 8.86 (1H, d, J=5.0 Hz), 8.64 (1H, dt, J=5.0, 1.6 Hz), 7.87(1H, m), 7.85-7.83 (2H, m), 7.72 (1H, dd, J=5.0, 1.3 Hz), 7.52-7.46 (1H,m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d,J=2.0 Hz), 5.61 (1H, dd, J=12.5, 2.1 Hz), 4.22 (1H, d, J=16.9 Hz),3.94-3.90 (1H, m), 2.94 (1H, d, J=12.5 Hz), 2.90-2.80 (2H, m), 2.73-2.66(1H, m), 2.57-2.53 (1H, m).

Example 11BF.(R)-(6-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 3.39 min, m+H 616.8; 1H NMR (400 MHz,CDCl₃): δ 8.60-8.58 (1H, m), 7.97 (1H, d, J=2.1 Hz), 7.85-7.80 (2H, m),7.76 (1H, dd, J=8.4, 2.1 Hz), 7.52 (1H, d, J=8.5 Hz), 7.48-7.40 (3H, m),7.27 (1H, m), 7.19-7.13 (2H, m), 6.50 (1H, d, J=2.1 Hz), 5.54 (1H, dd,J=12.6, 2.0 Hz), 4.22 (1H, d, J=16.9 Hz), 3.93-3.88 (1H, m), 2.90-2.80(3H, m), 2.68-2.61 (1H, m), 2.56-2.51 (1H, m).

Example 11BG.(R)-(6-((3-chloro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.81 min, m+H 563.0; 1H NMR (400 MHz,CDCl₃): δ 8.64 (1H, ddd, J=4.7, 1.8, 0.9 Hz), 7.91-7.87 (1H, m), 7.83(1H, td, J=7.4, 1.7 Hz), 7.64 (1H, d, J=1.8 Hz), 7.50-7.40 (4H, m), 7.31(1H, s), 7.29 (1H, s), 7.20-7.12 (2H, m), 6.48 (1H, d, J=2.1 Hz), 5.52(1H, dd, J=12.2, 2.1 Hz), 4.29 (1H, d, J=16.9 Hz), 3.86-3.82 (1H, m),2.92-2.70 (3H, m), 2.54-2.47 (2H, m), 2.40 (3H, s).

Example 11BH.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(2-(pyrrolidin-1-yl)pyridin-4-yl)methanone

LCMS (Method F, ES-API): RT 2.11 min, m+H=619.9; 1H NMR (400 MHz,CDCl₃): δ 8.14 (1H, d, J=5.0 Hz), 7.69-7.59 (2H, m), 7.46 (1H, s),7.40-7.35 (3H, m), 7.21-7.15 (2H, m), 6.50 (1H, dd, J=5.2, 1.2 Hz), 6.39(2H. d, J=14.0 Hz), 4.56 (1H, dd, J=11.4, 1.6 Hz), 3.88-3.87 (1H, m),3.36-3.30 (5H, m), 2.70 (1H, d, J=16.9 Hz), 2.48-2.36 (4H, m), 1.97-1.89(4H, m).

Example 11BI.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.42 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.89 (1H, d, J=5.0 Hz), 8.14 (1H, m), 7.70-7.68 (1H, m),7.47-7.42 (2H, m), 7.39 (1H, d, J=2.3 Hz), 7.31 (1H, s), 7.21-7.15 (2H,m), 6.57 (1H, d, J=2.2 Hz), 6.52 (1H, d, J=2.1 Hz), 5.56 (1H, dd,J=12.6, 2.1 Hz), 4.24 (1H, d, J=16.9 Hz), 3.96 (3H, s), 3.89-3.85 (1H,m), 2.96 (1H, d, J=16.9 Hz), 2.93 (1H, d, J=12.4 Hz), 2.88-2.79 (1H, m),2.68-2.61 (1H, m), 2.51-2.47 (1H, m).

Example 11BJ.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.15 min, m+H=519.0; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.91-7.88 (1H, m),7.85-7.81 (1H, m), 7.48-7.42 (3H, m), 7.38 (1H, d, J=2.2 Hz), 7.31 (1H,s), 7.20-7.14 (2H, m), 6.58 (1H, d, J=2.2 Hz), 6.50 (1H, d, J=2.1 Hz),5.54 (1H, dd, J=12.5, 2.0 Hz), 4.34 (1H, d, J=16.9 Hz), 3.95 (3H, s),3.88-3.84 (1H, m), 2.94 (1H, d, J=16.9 Hz), 2.91 (1H, d, J=12.4 Hz),2.88-2.79 (1H, m), 2.67-2.60 (1H, m), 2.50-2.45 (1H, m).

Example 11BK.(R)-(1-(4-fluorophenyl)-6-((5-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.36 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.83 (1H, d, J=4.9 Hz), 8.14-8.13 (1H, m), 7.73 (1H, s), 7.68(1H, dd, J=4.9, 1.1 Hz), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.20-7.14 (2H,m), 6.51 (1H, d, J=2.1 Hz), 5.45 (1H, dd, J=12.3, 2.0 Hz), 4.19 (1H, d,J=16.9 Hz), 3.85-3.80 (1H, m), 2.93 (1H, d, J=16.9 Hz), 2.86-2.78 (2H,m), 2.59-2.50 (2H, m), 2.38 (3H, s).

Example 11BL.(R)-3-((1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS (Method F, ES-API): RT 2.68 min, m+H=608.0; 1H NMR (400 MHz,CDCl₃): δ 8.90 (1H, d, J=5.0 Hz), 8.13 (1H, m), 7.98 (1H, m), 7.91-7.89(1H, m), 7.84-7.81 (1H, m), 7.74 (1H, dd, J=5.0, 0.9 Hz), 7.65-7.61 (1H,m), 7.45-7.40 (2H, m), 7.29 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d,J=2.0 Hz), 5.53 (1H, dd, J=12.3, 2.0 Hz), 4.18 (1H, d, J=16.9 Hz),3.91-3.87 (1H, m), 2.90 (1H, d, J=16.9 Hz), 2.88-2.77 (2H, m), 2.58-2.51(2H, m).

Example 11BM.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.55 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.81 (1H, d, J=4.9 Hz), 8.12 (1H, m), 7.70-7.69 (1H, m),7.47-7.41 (2H, m), 7.35 (1H, d, J=2.1 Hz), 7.28 (1H, s), 7.21-7.15 (2H,m), 6.62 (1H, d, J=2.1 Hz), 6.54 (1H, d, J=2.0 Hz), 5.50 (1H, dd,J=12.4, 2.0 Hz), 4.18 (1H, d, J=16.9 Hz), 3.95 (3H, s), 3.94-3.90 (1H,m), 3.02 (1H, d, J=12.6 Hz), 2.92 (1H, d, J=16.9 Hz), 2.86-2.74 (2H, m),2.60-2.55 (1H, m).

Example 11BN.(R)-(6-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.44 min, m+H=601.2; 1H NMR (400 MHz,CDCl₃): δ 8.84 (1H, d, J=4.9 Hz), 8.13 (1H, br s), 7.69 (1H, dd, J=4.9,1.0 Hz), 7.61 (1H, s), 7.47-7.41 (2H, m), 7.28 (1H, s), 7.20-7.14 (2H,m), 6.51 (1H, d, J=2.0 Hz), 5.46 (1H, dd, J=12.3, 1.9 Hz), 4.16 (1H, d,J=16.9 Hz), 3.85-3.79 (1H, m), 3.71 (3H, s), 2.92 (1H, d, J=16.9 Hz),2.87-2.76 (2H, m), 2.58-2.50 (2H, m), 2.34 (3H, s).

Example 11BO.(R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.28 min, m+H=573.2; 1H NMR (400 MHz,CDCl₃): δ 11.0 (1H, br s), 8.86 (1H, d, J=4.9 Hz), 8.15 (1H, m), 7.83(2H, s), 7.71-7.69 (1H, m), 7.46-7.41 (2H, m), 7.31 (1H, s), 7.20-7.14(2H, m), 6.50 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.1, 2.0 Hz), 4.20(1H, d, J=16.9 Hz), 3.82-3.78 (1H, m), 2.92 (1H, d, J=16.9 Hz),2.87-2.78 (1H, m), 2.67 (1H, d, J=12.2 Hz), 2.52-2.40 (2H, m).

Example 11BP.(R)-(1-(4-fluorophenyl)-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.47 min, m+H 587.0; 1H NMR (400 MHz,CDCl₃): δ 8.61 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 7.90-7.80 (2H, m), 7.74(1H, s), 7.48-7.42 (3H, m), 7.28 (1H, s), 7.21-7.14 (2H, m), 6.51 (1H,d, J=2.0 Hz), 5.50 (1H, dd, J=12.6, 2.0 Hz), 4.26 (1H, d, J=16.8 Hz),3.92 (3H, s), 3.89-3.85 (1H, m), 2.98 (1H, d, J=12.6 Hz), 2.90 (1H, d,J=16.8 Hz), 2.86-2.68 (2H, m), 2.56-2.46 (1H, m).

Example 11BQ.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.85 min, m+H=637.2; 1H NMR (400 MHz,CDCl₃): δ 8.87 (1H, d, J=4.9 Hz), 8.14 (1H, br s), 7.72 (1H, dd, J=4.9,1.0 Hz), 7.46-7.41 (2H, m), 7.37-7.31 (2H, m), 7.29 (1H, s), 7.20-7.15(2H, m), 6.52 (1H, d, J=2.1 Hz), 5.50 (1H, dd, J=12.3, 2.1 Hz), 4.17(1H, d, J=16.9 Hz), 3.88-3.83 (1H, m), 2.91 (1H, d, J=16.9 Hz),2.88-2.78 (2H, m), 2.61-2.51 (2H, m).

Example 11BR.(R)-(1-(4-chlorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.60 min, m+H=603.2; 1H NMR (400 MHz,CDCl₃): δ 8.88 (1H, d, J=4.9 Hz), 8.14 (1H, br s), 7.68 (1H, dd, J=4.9,1.0 Hz), 7.47-7.41 (4H, m), 7.38 (1H, d, J=2.3 Hz), 7.32 (1H, s), 6.56(1H, d, J=2.3 Hz), 6.55 (1H, d, J=2.0 Hz), 5.55 (1H, dd, J=12.5, 2.0Hz), 4.23 (1H, d, J=16.9 Hz), 3.96 (3H, s), 3.89-3.85 (1H, m), 2.95 (1H,d, J=16.9 Hz), 2.94 (1H, d, J=12.5 Hz), 2.89-2.80 (1H, m), 2.69-2.63(1H, m), 2.51-2.47 (1H, m).

Example 11BS.(R)-(6-((1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.25 min, m+H=505.0; 1H NMR (400 MHz,CDCl₃): δ 11.12 (1H, br. s), 8.65 (1H, ddd, J=4.7, 1.6, 1.0 Hz), 8.36(1H, d, J=0.6 Hz), 7.88-7.81 (2H, m), 7.78 (1H, d, J=0.6 Hz), 7.51-7.39(3H, m), 7.31 (1H, s), 7.20-7.13 (2H, m), 6.50 (1H, d, J=2.0 Hz), 5.50(1H, dd, J=12.1, 2.0 Hz), 4.24 (1H, d, J=17.0 Hz), 3.86-3.78 (1H, m),2.91 (1H, d, J=17.0 Hz), 2.86-2.74 (2H, m), 2.64-2.45 (2H, m).

Example 11BT.(R)-(6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1-(4-(trifluoromethyl)phenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.48 min, m+H=569.0; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 7.89 (1H, dt, J=7.9, 1.4Hz), 7.83 (1H, td, J=7.6, 1.8 Hz), 7.74 (2H, d, J=8.4 Hz), 7.63 (2H, d,J=8.4 Hz), 7.46 (1H, ddd, J=7.6, 4.8, 1.4 Hz), 7.38 (1H, d, J=2.3 Hz),7.37 (1H, s), 6.59 (1H, br. d, J=2.3 Hz), 6.58 (1H, br. d, J=2.3 Hz),5.53 (1H, dd, J=12.5, 2.0 Hz), 4.37 (1H, d, J=17.1 Hz), 3.96 (3H, s),3.87 (1H, ddt, J=8.5, 4.1, 2.0 Hz), 2.98-2.80 (3H, m), 2.66 (1H, ddd,J=12.6, 11.1, 3.5 Hz), 2.53-2.44 (1H, m).

Example 11BU.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.76 min, m+H=556.9; 1H NMR (400 MHz,CDCl₃): δ 8.87 (1H, d, J=2.2 Hz), 8.24 (1H, d, J=2.2 Hz), 7.56-7.46 (2H,m), 7.46-7.39 (2H, m), 7.29-7.23 (2H, m), 7.19-7.12 (2H, m), 6.52 (1H,d, J=2.1 Hz), 5.45 (1H, dd, J=12.4, 2.1 Hz), 4.15 (1H, d, J=17.0 Hz),3.89-3.84 (1H, m), 2.92-2.80 (2H, m), 2.73 (1H, d, J=12.5 Hz), 2.57-2.50(2H, m).

Example 11BV.(R)-(6-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.28 min, m+H=601.1; 1H NMR (400 MHz,CDCl₃): δ 8.87 (1H, d, J=5.0 Hz), 8.15-8.11 (1H, m), 7.70-7.65 (1H, m),7.49-7.40 (2H, m), 7.30 (1H, s), 7.21-7.14 (2H, m), 6.51 (1H, d, J=2.1Hz), 5.54 (1H, dd, J=12.6, 2.1 Hz), 4.23 (1H, d, J=17.2 Hz), 3.83 (1H,ddt, J=8.5, 4.0, 2.1 Hz), 3.58 (3H, s), 2.99 (1H, d, J=12.6 Hz), 2.97(1H, d, J=17.2 Hz), 2.82 (1H, tdd, J=14.8, 5.9, 2.4 Hz), 2.70-2.61 (1H,m), 2.47-2.43 (1H, m), 2.37 (3H, s).

Example 11BW.(R)-(6-((1,2-dimethyl-1H-imidazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.20 min, m+H=601.0; 1H NMR (400 MHz,CDCl₃): δ 8.76 (1H, d, J=5.0 Hz), 8.04 (1H, s), 7.72-7.65 (1H, m),7.45-7.41 (3H, m), 7.24 (1H, s), 7.22-7.13 (2H, m), 6.55 (1H, s), 5.60(1H, dd, J=12.9, 2.0 Hz), 4.08 (1H, d, J=16.9 Hz), 4.01-3.96 (1H, m),3.40 (3H, s), 3.12 (1H, d, J=13.0 Hz), 2.96-2.82 (3H, m), 2.69-2.59 (1H,m), 2.12 (3H, s).

Example 11BX.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-imidazol-2-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.49 min, m+H=587.0; 1H NMR (400 MHz,CDCl₃): δ 8.83 (1H, d, J=5.0 Hz), 8.15-8.13 (1H, m), 7.70-7.64 (1H, m),7.51-7.42 (2H, m), 7.30 (1H, s), 7.23-7.14 (2H, m), 7.00 (1H, d, J=1.1Hz), 6.90 (1H, d, J=1.1 Hz), 6.57 (1H, d, J=2.1 Hz), 5.60 (1H, dd,J=13.0, 2.1 Hz), 4.24 (1H, d, J=17.0 Hz), 3.93 (1H, ddt, J=9.2, 4.2, 2.1Hz), 3.80 (3H, s), 3.57 (1H, d, J=13.1 Hz), 3.28-3.15 (1H, m), 3.01 (1H,d, J=17.0 Hz), 2.87 (1H, dddd, J=15.1, 12.6, 6.1, 2.4 Hz), 2.58-2.51(1H, m).

Example 11BY.(R)-(6-((1-ethyl-1H-imidazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.34 min, m+H=601.1; 1H NMR (400 MHz,CDCl₃): δ 8.87 (1H, d, J=4.9 Hz), 8.14 (1H, m), 7.67 (1H, dd, J=4.9, 1.0Hz), 7.49 (1H, d, J=1.4 Hz), 7.47-7.42 (2H, m), 7.40 (1H, d, J=1.4 Hz),7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.58 (1H, dd,J=12.4, 2.1 Hz), 4.24 (1H, d, J=16.9 Hz), 4.02 (2H, q, J=7.4 Hz),3.88-3.83 (1H, m), 3.03 (1H, d, J=12.4 Hz), 2.96 (1H, d, J=16.9 Hz),2.87-2.78 (1H, m), 2.72-2.65 (1H, m), 2.50-2.46 (1H, m), 1.49 (3H, t,J=7.4 Hz).

Example 11BZ.(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.34 min, m+H=539.0; 1H NMR (400 MHz,CDCl₃): δ 8.89 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=2.2 Hz), 7.73 (1H, s),7.67 (1H, d, J=0.7 Hz), 7.48-7.39 (2H, m), 7.30 (1H, s), 7.21-7.12 (2H,m), 6.52 (1H, d, J=2.2 Hz), 5.42 (1H, dd, J=12.1, 2.2 Hz), 4.25-4.13(3H, m), 3.80 (1H, ddt, J=10.5, 6.4, 2.0 Hz), 2.94-2.81 (2H, m), 2.63(1H, d, J=12.1 Hz), 2.55-2.38 (2H, m), 1.52 (3H, t, J=7.3 Hz).

Example 11CA.(R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.36 min, m+H=547.2; 1H NMR (400 MHz,CDCl₃): δ 8.66 (1H, dq, J=4.8, 0.8 Hz), 7.90 (1H, dt, J=8.0, 1.2 Hz),7.84 (1H, td, J=7.6, 1.6 Hz), 7.68 (2H, dd, J=14.0, 0.8), 7.49-7.42 (3H,m), 7.30 (1H, s), 7.19-7.14 (2H, m), 6.49 (1H, d, J=2.0 Hz), 5.46 (1H,dd, J=12.0, 2.0 Hz), 4.32 (1H, d, J=16.8 Hz), 4.07 (2H, t, J=7.0 Hz),3.79-3.75 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.88-2.80 (1H, m), 2.67 (1H,d, J=12.0 Hz), 2.50-2.39 (2H, m), 1.89 (2H, sex, J=7.6 Hz), 0.91 (3H, t,J=7.6 Hz).

Example 11CB.(R)-(1-(4-fluorophenyl)-6-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.19 min, m+H=563.3; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, d, J=4.9, 1.7, 0.9 Hz), 7.92-7.89 (1H, m), 7.84 (1H,dt, J=7.5, 1.7 Hz), 7.81 (1H, s), 7.66 (1H, d, J=0.5 Hz), 7.49-7.42 (3H,m), 7.31 (1H, s), 7.19-7.13 (2H, m), 6.49 (1H, d, J=2.1 Hz), 5.46 (1H,dd, J=12.1, 2.1 Hz), 4.32 (1H, d, J=16.9 Hz), 4.28 (2H, dd, J=4.9 Hz),3.79-3.75 (1H, m), 3.71 (2H, dd, J=4.9 Hz), 3.32 (3H, s), 2.91 (1H, d,J=16.9 Hz), 2.88-2.78 (1H, m), 2.66 (1H, d, J=12.0 Hz), 2.51-2.39 (2H,m).

Example 11CC.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-pyrazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.52 min, m+H=586.1; 1H NMR (400 MHz,CDCl₃): δ 7.88 (1H, s), 7.87 (1H, d, J=1.8 Hz), 7.84 (1H, d, J=0.5 Hz),7.63-7.58 (2H, m), 7.46-7.41 (2H, m), 7.35 (1H, s), 7.22-7.16 (2H, m),6.50 (1H, s), 4.55 (1H, dd, J=11.4, 1.7 Hz), 3.89 (3H, s), 3.89-3.82(1H, m), 3.29 (1H, d, J=17.2 Hz), 2.76 (1H, d, J=17.2 Hz), 2.62-2.45(3H, m), 2.42-2.37 (1H, m).

Example 11CD.(R)-(1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.41 min, m+H=547.1; 1H NMR (400 MHz,CDCl₃): δ 8.67 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 7.90 (1H, ddd, J=7.9, 1.3,0.9 Hz), 7.84 (1H, td, J=7.5, 1.8 Hz), 7.73 (1H, s), 7.66 (1H, d, J=0.7Hz), 7.52-7.41 (3H, m), 7.30 (1H, s), 7.21-7.12 (2H, m), 6.50 (1H, d,J=2.1 Hz), 5.47 (1H, dd, J=12.0, 2.1 Hz), 4.49 (1H, hept, J=6.9 Hz),4.32 (1H, d, J=17.0 Hz), 3.80-3.74 (1H, m), 2.93 (1H, d, J=17.0 Hz),2.88-2.79 (1H, m), 2.68 (1H, d, J=12.0 Hz), 2.58-2.39 (2H, m), 1.52 (6H,d, J=6.9 Hz).

Examples 11CE, 11CF and 11CG

11CE (R)-(1-(4-fluorophenyl)-6- ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

11CF (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

11CG (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 89. LCMS (Method F, ES-API):RT 2.55 min, m+H=588.0; 1H NMR (400 MHz, CDCl₃): δ 8.89 (1H, dt, J=5.0,0.8 Hz), 8.15-8.13 (1H, m), 7.81 (1H, s), 7.70 (1H, ddd, J=5.1, 1.7, 0.8Hz), 7.48-7.42 (2H, m), 7.30 (1H, s), 7.22-7.13 (2H, m), 6.54 (1H, d,J=2.2 Hz), 5.59 (1H, dd, J=12.7, 2.2 Hz), 4.25 (3H, s), 4.22 (1H, d,J=17.0 Hz), 3.90 (1H, ddt, J=10.6, 6.0, 2.0 Hz), 2.99 (1H, d, J=12.7Hz), 2.95 (1H, d, J=17.0 Hz), 2.84 (1H, tdd, J=12.7, 5.9, 3.0 Hz),2.74-2.67 (1H, m), 2.52 (1H, br. dt, J=14.6, 2.7 Hz).

Prepared from Preparation 2 of Intermediate 89. LCMS (Method F, ES-API):RT 2.50 min, m+H=588.2; 1H NMR (400 MHz, CDCl₃): δ 8.80 (1H, d, J=4.9Hz), 8.11 (1H, m), 7.91 (1H, s), 7.73-7.71 (1H, m), 7.47-7.41 (2H, m),7.28 (1H, s), 7.21-7.16 (2H, m), 6.56 (1H, s), 5.51 (1H, dd, J=12.7, 2.1Hz), 4.13 (1H, d, J=16.9 Hz), 4.11 (3H, s), 4.01-3.93 (1H, m), 3.09 (1H,d, J=12.7 Hz), 2.92 (1H, d, J=16.9 Hz), 2.87-2.81 (2H, m), 2.65-2.60(1H, m).

Prepared from Preparation 3 of Intermediate 89. LCMS (Method F, ES-API):RT 2.41 min, m+H=588.2; 1H NMR (400 MHz, CDCl₃): δ 8.87 (1H, d, J=4.9Hz), 8.15 (1H, m), 7.89 (1H, s), 7.70-7.69 (1H, m), 7.48-7.43 (2H, m),7.31 (1H, s), 7.21-7.15 (2H, m), 6.54 (1H, s), 5.61 (1H, dd, J=12.5, 2.0Hz), 4.23 (1H, d, J=16.9 Hz), 4.15 (3H, s), 3.95-3.87 (1H, m), 3.14 (1H,d, J=12.5 Hz), 2.96 (1H, d, J=16.9 Hz), 2.88-2.78 (2H, m), 2.57-2.48(1H, m).

Examples 11CH, 11CI and 11CJ

11CH (R)-(6-((2-ethyl-2H-1,2,3- triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

11CI (R)-(6-((1-ethyl-1H-1,2,3- triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

11CJ (R)-(6-((1-ethyl-1H-1,2,3- triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 90. LCMS (Method F, ES-API):RT 2.44 min, m+H=534.0; 1H NMR (400 MHz, CDCl₃): δ 8.68 (1H, ddd, J=4.8,1.7, 0.9 Hz), 7.88 (1H, ddd, J=7.9, 1.7, 0.9 Hz), 7.84 (1H, td, J=7.4,1.7 Hz), 7.80 (1H, s), 7.51-7.40 (3H, m), 7.31 (1H, s), 7.22-7.12 (2H,m), 6.51 (1H, d, J=2.1 Hz), 5.61 (1H, dd, J=12.7, 2.1 Hz), 4.51 (2H, q,J=7.3 Hz), 4.32 (1H, d, J=17.0 Hz), 3.90 (1H, ddt, J=11.0, 6.0, 2.0 Hz),3.00-2.90 (2H, m), 2.84 (1H, tdd, J=12.7, 6.0, 3.0 Hz), 2.70 (1H, ddd,J=12.7, 11.0, 3.3 Hz), 2.50 (1H, dt, J=14.3, 3.0 Hz), 1.59 (3H, t, J=7.3Hz).

Prepared from Preparation 2 of Intermediate 90. LCMS (Method F, ES-API):RT 2.42 min, m+H=534.1; 1H NMR (400 MHz, CDCl₃): δ 8.61-8.55 (1H, m),7.88 (1H, s), 7.86-7.79 (2H, m), 7.52-7.40 (3H, m), 7.27 (1H, br. s),7.22-7.13 (2H, m), 6.54 (1H, br. s), 5.62 (1H, dd, J=12.6, 2.0 Hz),4.50-4.36 (2H, m), 4.21 (1H, d, J=16.9 Hz), 3.98-3.89 (1H, m), 3.13 (1H,d, J=12.7 Hz), 2.96-2.76 (3H, m), 2.64-2.56 (1H, m), 1.51 (3H, t, J=7.3Hz).

Prepared from Preparation 3 of Intermediate 90. LCMS (Method F, ES-API):RT 2.32 min, m+H=534.1; 1H NMR (400 MHz, CDCl₃): δ 8.66 (1H, ddd, J=4.8,1.8, 0.9 Hz), 7.92-7.87 (2H, m), 7.83 (1H, td, J=7.7, 1.8 Hz), 7.49-7.40(3H, m), 7.30 (1H, s), 7.21-7.12 (2H, m), 6.51 (1H, br. s), 5.59 (1H,dd, J=12.6, 2.1 Hz), 4.45 (2H, q, J=7.4 Hz), 4.31 (1H, d, J=16.9 Hz),3.98-3.87 (1H, m), 3.14 (1H, d, J=12.6 Hz), 2.94 (1H, d, J=16.9 Hz),2.87-2.78 (2H, m), 2.56-2.44 (1H, m), 1.59 (3H, t, J=7.4 Hz).

Examples 11CK, 11CL and 11CM

11CK (R)-(6-((2-ethyl-2H-1,2,3- triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

11CL (R)-(6-((1-ethyl-1H-1,2,3- triazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

11CM (R)-(6-((1-ethyl-1H-1,2,3- triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 90. LCMS (Method F, ES-API):RT 2.67 min, m+H=602.0; 1H NMR (400 MHz, CDCl₃): δ 8.89 (1H, d, J=5.1Hz), 8.16-8.12 (1H, m), 7.81 (1H, s), 7.71 (1H, ddd, J=5.0, 1.8, 0.7Hz), 7.49-7.40 (2H, m), 7.30 (1H, s), 7.23-7.15 (2H, m), 6.54 (1H, d,J=2.1 Hz), 5.59 (1H, dd, J=12.7, 2.1 Hz), 4.51 (2H, q, J=7.3 Hz), 4.22(1H, d, J=17.0 Hz), 3.95-3.84 (1H, m), 2.97 (1H, d, J=12.7 Hz), 2.95(1H, d, J=17.0 Hz), 2.89-2.78 (1H, m), 2.73-2.66 (1H, m), 2.58-2.47 (1H,m), 1.59 (3H, t, J=7.3 Hz).

Prepared from Preparation 2 of Intermediate 90. LCMS (Method F, ES-API):RT 2.62 min, m+H=602.1; 1H NMR (400 MHz, CDCl₃): δ 8.81 (1H, d, J=5.1Hz), 8.12-8.11 (1H, m), 7.89 (1H, s), 7.72 (1H, ddd, J=5.1, 1.8, 0.7Hz), 7.48-7.39 (2H, m), 7.28 (1H, s), 7.24-7.13 (2H, m), 6.57 (1H, br.s), 5.54 (1H, dd, J=12.8, 2.1 Hz), 4.53-4.40 (2H, m), 4.14 (1H, d,J=16.9 Hz), 4.01-3.90 (1H, m), 3.11 (1H, d, J=12.8 Hz), 2.92 (1H, d,J=16.9 Hz), 2.86-2.79 (2H, m), 2.68-2.55 (1H, m), 1.52 (3H, t, J=7.2Hz).

Prepared from Preparation 3 of Intermediate 90. LCMS (Method F, ES-API):RT 2.53 min, m+H=602.1; 1H NMR (400 MHz, CDCl₃): δ 8.88 (1H, br. d,J=5.1 Hz), 8.15-8.14 (1H, m), 7.91 (1H, s), 7.69 (1H, ddd, J=5.1, 1.8,0.8 Hz), 7.49-7.41 (2H, m), 7.31 (1H, s), 7.23-7.13 (2H, m), 6.54 (1H,br. s), 5.62 (1H, dd, J=12.8, 2.1 Hz), 4.46 (2H, q, J=7.4 Hz), 4.23 (1H,d, J=17.0 Hz), 3.94-3.88 (1H, m), 3.17 (1H, d, J=12.8 Hz), 2.97 (1H, d,J=17.0 Hz), 2.89-2.80 (2H, m), 2.57-2.46 (1H, m), 1.60 (3H, t, J=7.4Hz).

Examples 11CN, 11CO and 11CP

11CN (R)-(1-(4-fluorophenyl)-6- ((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(pyridin-2- yl)methanone

11CO (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(pyridin-2- yl)methanone

11CP (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 91. LCMS (Method F, ES-API):RT 2.54 min, m+H=548.2; 1H NMR (400 MHz, CDCl₃): δ 8.68 (1H, ddd, J=4.9,1.6, 0.9 Hz), 7.88 (1H, ddd, J=7.9, 1.4, 0.9 Hz), 7.83 (1H, dt, J=7.4,1.6 Hz), 7.80 (1H, s), 7.49-7.42 (3H, m), 7.30 (1H, s), 7.20-7.14 (2H,m), 6.51 (1H, d, J=2.1 Hz), 5.60 (1H, dd, J=12.5, 2.0 Hz), 4.42 (2H, t,J=7.1 Hz), 4.32 (1H, d, J=16.9 Hz), 3.92-3.87 (1H, m), 2.95 (1H, d,J=12.5 Hz), 2.92 (1H, d, J=16.9 Hz), 2.89-2.80 (1H, m), 2.71-2.64 (1H,m), 2.52-2.47 (1H, m), 2.00 (2H, sext, J=7.1 Hz), 0.93 (3H, t, J=7.1Hz).

Prepared from Preparation 2 of Intermediate 91. LCMS (Method F, ES-API):RT 2.47 min, m+H=548.2; 1H NMR (400 MHz, CDCl₃): δ 8.59 (1H, ddd, J=4.9,1.6, 0.9 Hz), 7.88 (1H, s), 7.87-7.81 (2H, m), 7.48 (1H, ddd, J=6.8,4.9, 2.1 Hz), 7.46-7.41 (2H, m), 7.27 (1H, s), 7.20-7.14 (2H, m), 6.54(1H, br s), 5.61 (1H, dd, J=12.7, 2.0 Hz), 4.40-4.29 (2H, m), 4.22 (1H,d, J=16.9 Hz), 3.97-3.89 (1H, m), 3.12 (1H, d, J=12.7 Hz), 2.91-2.81(3H, m), 2.64-2.56 (1H, m), 1.92 (2H, dsext, J=7.1, 0.7 Hz), 0.93 (3H,t, J=7.1 Hz).

Prepared from Preparation 3 of Intermediate 91. LCMS (Method F, ES-API):RT 2.37 min, m+H=548.2; 1H NMR (400 MHz, CDCl₃): δ 8.66 (1H, ddd, J=4.7,1.6, 0.9 Hz), 7.91-7.88 (2H, m), 7.83 (1H, dt, J=7.5, 1.6 Hz), 7.48-7.42(3H, m), 7.30 (1H, s), 7.19-7.14 (2H, m), 6.51 (1H, s), 5.60 (1H, dd,J=12.5, 2.0 Hz), 4.35 (2H, t, J=7.1 Hz), 4.32 (1H, d, J=16.9 Hz),3.97-3.88 (1H, m), 3.12 (1H, d, J=12.5 Hz), 2.94 (1H, d, J=16.9 Hz),2.88-2.79 (2H, m), 2.55-2.46 (1H, m), 1.96 (2H, sext, J=7.1 Hz), 0.97(3H, t, J=7.1 Hz).

Examples 11CQ, 11CR and 11CS

11CQ (R)-(1-(4-fluorophenyl)-6- ((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4-yl)methanone

11CR (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4-yl)methanone

11CS (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4-yl)methanone

Prepared from Preparation 1 of Intermediate 91. LCMS (Method F, ES-API):RT 2.45 min, m+H=554.2; 1H NMR (400 MHz, CDCl₃): δ 8.90 (1H, d, J=2.1Hz), 8.25 (1H, d, J=2.1 Hz), 7.82 (1H, s), 7.47-7.42 (2H, m), 7.30 (1H,s), 7.20-7.14 (2H, m), 6.54 (1H, d, J=2.1 Hz), 5.55 (1H, dd, J=12.7, 2.0Hz), 4.43 (2H, t, J=7.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.95-3.90 (1H, m),2.93-2.85 (3H, m), 2.69-2.63 (1H, m), 2.53-2.49 (1H, m), 2.01 (2H, sext,J=7.1 Hz), 0.94 (3H, t, J=7.1 Hz).

Prepared from Preparation 2 of Intermediate 91. LCMS (Method F, ES-API):RT 2.38 min, m+H=554.2; 1H NMR (400 MHz, CDCl₃): δ 8.81 (1H, d, J=2.2Hz), 8.22 (1H, d, J=2.2 Hz), 7.89 (1H, s), 7.47-7.42 (2H, m), 7.28 (1H,s), 7.21-7.15 (2H, m), 6.57 (1H, br s), 5.48 (1H, dd, J=12.8, 2.0 Hz),4.39-4.28 (2H, m), 4.12 (1H, d, J=16.9 Hz), 4.01-3.93 (1H, m), 3.06 (1H,d, J=12.8 Hz), 2.92-2.83 (3H, m), 2.66-2.57 (1H, m), 1.93 (2H, dsext,J=7.1, 0.6 Hz), 0.94 (3H, t, J=7.1 Hz).

Prepared from Preparation 3 of Intermediate 91. LCMS (Method F, ES-API):RT 2.29 min, m+H=554.2; 1H NMR (400 MHz, CDCl₃): δ: 8.88 (1H, d, J=2.1Hz), 8.26 (1H, d, J=2.1 Hz), 7.90 (1H, s), 7.48-7.42 (2H, m), 7.30 (1H,s), 7.20-7.14 (2H, m), 6.54 (1H, d, J=1.4 Hz), 5.55 (1H, dd, J=12.7, 2.0Hz), 4.37 (2H, t, J=7.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.96-3.91 (1H, m),3.06 (1H, d, J=12.7 Hz), 2.94-2.80 (3H, m), 2.57-2.48 (1H, m), 1.97 (2H,sext, J=7.1 Hz), 0.98 (3H, t, J=7.1 Hz).

Examples 11CT, 11CU and 11CV

11CT (R)-(1-(4-fluorophenyl)-6- ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin- 4a-yl)(pyridin-2- yl)methanone

11CU (R)-(1-(4-fluorophenyl)-6- ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin- 4a-yl)(pyridin-2- yl)methanone

11CV (R)-(1-(4-fluorophenyl)-6- ((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin- 4a-yl)(pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 92. LCMS (Method F, ES-API):RT 2.56 min, m+H=548; 1H NMR (400 MHz, CDCl₃): δ 8.68 (ddd, J=4.7, 1.8,1.0 Hz, 1H), 7.92-7.81 (m, 2H), 7.79 (s, 1H), 7.52-7.39 (m, 3H), 7.30(d, J=0.8 Hz, 1H), 7.22-7.11 (m, 2H), 6.52 (d, J=2.2 Hz, 1H), 5.61 (dd,J=12.7, 2.0 Hz, 1H), 4.86 (hept, J=6.7 Hz, 1H), 4.33 (d, J=17.0 Hz, 1H),3.91 (ddt, J=10.8, 6.1, 2.1 Hz, 1H), 3.00-2.78 (m, 3H), 2.69 (ddd,J=12.6, 11.0, 3.3 Hz, 1H), 2.50 (dt, J=14.8, 2.7 Hz, 1H), 1.6 (d, J=6.6Hz, 6H).

Prepared from Preparation 2 of Intermediate 92. LCMS (Method F, ES-API):RT 2.49 min, m+H=548; 1H NMR (400 MHz, CDCl₃): δ 8.64-8.59 (m, 1H), 7.86(s, 1H), 7.85-7.82 (m, 2H), 7.54-7.47 (m, 1H), 7.46-7.41 (m, 2H),7.29-7.27 (m, 1H), 7.21-7.13 (m, 2H), 6.55 (d, J=1.5 Hz, 1H), 5.67 (dd,J=12.7, 2.1 Hz, 1H), 4.95 (hept, J=6.7 Hz, 1H), 4.21 (d, J=16.8 Hz, 1H),3.96-3.84 (m, 1H), 3.14 (d, J=12.7 Hz, 1H), 2.95-2.84 (m, 3H), 2.61 (m,1H), 1.56 (d, J=6.7 Hz, 3H), 1.53 (d, J=6.7 Hz, 3H).

Prepared from Preparation 3 of Intermediate 92. LCMS (Method F, ES-API):RT 2.43 min, m+H=548.1; 1H NMR (400 MHz, CDCl₃): δ 8.67 (1H, ddd, J=4.8,1.8, 0.9 Hz), 7.91-7.86 (2H, m), 7.83 (1H, td, J=7.7, 1.8 Hz), 7.50-7.41(3H, m), 7.31 (1H, s), 7.21-7.13 (2H, m), 6.52 (1H, br. s), 5.61 (1H,dd, J=12.6, 2.1 Hz), 4.86 (1H, hept, J=6.7 Hz), 4.32 (1H, d, J=16.9 Hz),3.97-3.89 (1H, m), 3.15 (1H, d, J=12.6 Hz), 2.94 (1H, d, J=16.9 Hz),2.91-2.78 (2H, m), 2.58-2.44 (1H, m), 1.61 (3H, d, J=6.7 Hz), 1.60 (3H,d, J=6.7 Hz).

Example 11CW.(R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.32 min, m+H=539.2; 1H NMR (400 MHz,CDCl₃): δ 8.81 (1H, d, J=2.1 Hz), 8.22 (1H, d, J=2.2 Hz), 7.47-7.42 (2H,m), 7.39 (1H, d, J=2.0 Hz), 7.28 (1H, s), 7.20-7.14 (2H, m), 6.63 (1H,d, J=2.0 Hz), 6.55 (1H, d, J=2.1 Hz), 5.46 (1H, dd, J=12.7, 2.0 Hz),4.34-4.17 (2H, m), 4.16 (1H, d, J=16.9 Hz), 3.94-3.89 (1H, m), 2.98 (1H,d, J=12.9 Hz), 2.92-2.75 (3H, m), 2.60-2.56 (1H, m), 1.41 (3H, t, J=7.2Hz).

Example 11CX.(R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.58 min, m+H=615.2; 1H NMR (400 MHz,CDCl₃): δ 8.88 (1H, d, J=5.0 Hz), 8.17-8.13 (1H, m), 7.73-7.66 (3H, m),7.47-7.40 (2H, m), 7.30 (1H, s), 7.22-7.12 (2H, m), 6.51 (1H, d, J=2.1Hz), 5.45 (1H, dd, J=12.1, 2.1 Hz), 4.21 (1H, d, J=17.0 Hz), 4.09 (2H,t, J=11.3 Hz), 3.78 (1H, ddd, J=10.6, 5.3, 3.1 Hz), 2.93 (1H, d, J=17.0Hz), 2.83 (1H, dddd, J=14.9, 12.5, 6.0, 2.4 Hz), 2.65 (1H, d, J=12.1Hz), 2.50 (1H, br. d, J=15.6 Hz), 2.41 (1H, ddd, J=12.8, 10.8, 3.5 Hz),1.90 (2H, sextet, J=7.4 Hz), 0.91 (3H, t, J=7.4 Hz).

Example 11CY.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.02 min, m+H=525.2; 1H NMR (400 MHz,CDCl₃): δ 8.88 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=2.2 Hz), 7.69 (1H, s),7.66 (1H, d, J=0.6 Hz), 7.47-7.40 (2H, m), 7.30 (1H, s), 7.21-7.12 (2H,m), 6.52 (1H, d, J=2.2 Hz), 5.41 (1H, dd, J=12.2, 2.2 Hz), 4.18 (1H, d,J=16.9 Hz), 3.93 (s, 3H), 3.80 (1H, ddt, J=8.5, 4.4, 1.9 Hz), 2.94-2.80(2H, m), 2.63 (1H, d, J=12.2 Hz), 2.56-2.38 (2H, m).

Example 11CZ.(R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS (Method F, ES-API): RT 2.31 min, m+H=553.2; 1H NMR (400 MHz,CDCl₃): δ 8.90 (1H, d, J=1.6 Hz), 8.27 (1H, d, J=2.0 Hz), 7.72 (1H, s),7.68 (1H, d, J=0.5 Hz), 7.46-7.42 (2H, m), 7.30 (1H, s), 7.20-7.15 (2H,m), 6.52 (1H, d, J=2.0 Hz), 5.43 (1H, dd, J=12.4, 2.0 Hz), 4.19 (1H, d,J=16.8 Hz), 4.09 (2H, t, J=7.1 Hz), 3.82-3.78 (1H, m), 2.94-2.81 (2H,m), 2.61 (1H, d, J=12.4 Hz), 2.53-2.48 (1H, m), 2.44-2.37 (1H, m), 1.91(2H, sext., J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz).

Example 11DA

Isomer A (R)-(1-(4-fluorophenyl)- 6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4- yl)methanone

Isomer B (R)-(1-(4-fluorophenyl)- 6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4- yl)methanone

Isomer C (R)-(1-(4-fluorophenyl)- 6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)- 4,4a,5,6,7,8-hexahydro- 1H-pyrazolo[3,4-g]isoquinolin-4a- yl)(thiazol-4- yl)methanone

Prepared from Preparation 1 of Intermediate 89. LCMS (Method F, ES-API):RT 2.16 min, m+H=526.2; 1H NMR (400 MHz, CDCl₃): δ 8.90 (1H, d, J=2.2Hz), 8.25 (1H, d, J=2.2 Hz), 7.82 (1H, s), 7.47-7.42 (2H, m), 7.30 (1H,s), 7.20-7.14 (2H, m), 6.54 (1H, d, J=2.1 Hz), 5.55 (1H, dd, J=12.7, 2.1Hz), 4.25 (3H, s), 4.20 (1H, d, J=16.9 Hz), 3.96-3.90 (1H, m), 2.93-2.85(3H, m), 2.73-2.66 (1H, m), 2.54-2.49 (1H, m).

Example 11DB

Isomer A (R)-(1-(4-fluorophenyl)-6- ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

Isomer B (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

Isomer C (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 89. LCMS (Method F, ES-API):RT 2.26 min, m+H=520.0; 1H NMR (400 MHz, CDCl₃): δ 8.67 (1H, ddd, J=4.9,1.6, 1.0 Hz), 7.88 (1H, ddd, J=8.0, 1.6, 1.0 Hz), 7.83 (1H, dt, J=7.4,1.6 Hz), 7.80 (1H, s), 7.49-7.42 (3H, m), 7.30 (1H, s), 7.20-7.14 (2H,m), 6.51 (1H, d, J=2.1 Hz), 5.60 (1H, dd, J=12.4, 2.0 Hz), 4.31 (1H, d,J=16.9 Hz), 4.24 (3H, s), 3.92-3.87 (1H, m), 2.98 (1H, d, J=12.6 Hz),2.93 (1H, d, J=16.9 Hz), 2.89-2.80 (1H, m), 2.74-2.68 (1H, m), 2.53-2.48(1H, m).

Example 11DC

Isomer A (R)-(1-(4-fluorophenyl)-6- ((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

Isomer B (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

Isomer C (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2- yl)methanone

Prepared from Preparation 1 of Intermediate 91. LCMS (Method F, ES-API):RT 2.75 min, m+H=616.2; 1H NMR (400 MHz, CDCl₃): δ 8.89 (1H, d, J=4.9Hz), 8.14 (1H, m), 7.82 (1H, s), 7.71-7.70 (1H, m), 7.47-7.42 (2H, m),7.30 (1H, s), 7.21-7.15 (2H, m), 6.53 (1H, d, J=2.1 Hz), 5.58 (1H, dd,J=12.5, 2.0 Hz), 4.42 (2H, t, J=7.1 Hz), 4.22 (1H, d, J=16.9 Hz),3.92-3.87 (1H, m), 2.96 (1H, br s), 2.93-2.92 (1H, m), 2.88-2.79 (1H,m), 2.70-2.64 (1H, m), 2.54-2.50 (1H, m), 2.01 (2H, sext, J=7.1 Hz),0.93 (3H, t, J=7.1 Hz).

Example 12.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

2-Bromothiazole (187 mg, 1.139 mmol) in dry ether (2 mL) was added tobutyllithium (1.6M in hexanes) (729 μl, 1.167 mmol) in dry ether (4 mL)at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. Asolution of (R)-methyl1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(200 mg, 0.373 mmol) in dry ether (4 mL) was added dropwise and thereaction mixture was stirred for 30 minutes at −78° C. Water (20 mL) wasadded and the reaction mixture was stirred at room temperature for 10minutes. The aqueous layer was extracted with ethyl acetate (3×30 mL).The combined organic extracts were washed with brine (30 mL), dried(magnesium sulfate), and solvent removed to give a yellow oil. The crudeproduct was purified first by chromatography on silica gel (gradient: 0to 40% isohexane in ethyl acetate) followed by preparative HPLC (Waters,Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mmcolumn, 40-65% acetonitrile in water) to afford(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone(127 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.73 min,m+H=589.0; 1H NMR (400 MHz, CDCl₃): δ 8.04 (1H, d, J=3.1 Hz), 7.97 (1H,s), 7.90 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.9 Hz), 7.70-7.59 (2H, m),7.46-7.39 (2H, m), 7.30 (1H, s), 7.13-7.19 (2H, m), 6.53 (1H, d, J=2.2Hz), 5.54 (1H, dd, J=12.4, 2.0 Hz), 4.21 (1H, d, J=16.8 Hz), 3.93-3.89(1H, m), 2.95-2.84 (2H, m), 2.80 (1H, d, J=12.5 Hz), 2.61-2.52 (2H, m).

The following examples were similarly prepared from the appropriateintermediates:

Example 12A.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.65 min, m+H=535.0; 1H NMR (400 MHz,CDCl₃): δ 8.05 (1H, d, J=3.1 Hz), 7.66 (1H, d, J=3.1 Hz), 7.54-7.47 (2H,m), 7.44-7.40 (2H, m), 7.36-7.34 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H,m), 6.51 (1H, d, J=2.3 Hz), 5.52 (1H, dd, J=12.3, 2.1 Hz), 4.22 (1H, d,J=16.8 Hz), 3.89-3.84 (1H, m), 2.93-2.84 (2H, m), 2.71 (1H, d, J=12.3Hz), 2.56-2.43 (2H, m), 2.41 (3H, s).

Example 12B.(R)-(1-(4-fluorophenyl)-6-((3-methoxyphenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.57 min, m+H=551.0; 1H NMR (400 MHz,CDCl₃): δ 8.04 (1H, d, J=3.1 Hz), 7.66 (1H, d, J=3.1 Hz), 7.44-7.35 (3H,m), 7.31-7.27 (2H, m), 7.21-7.14 (3H, m), 7.07 (1H, ddd, J=8.2, 2.6, 1.0Hz), 6.52 (1H, d, J=2.1 Hz), 5.50 (1H, dd, J=12.4, 2.1 Hz), 4.22 (1H, d,J=16.8 Hz), 3.89-3.83 (4H, m), 2.93-2.82 (2H, m), 2.74 (1H, d, J=12.4Hz), 2.53-2.47 (2H, m).

Example 12C.(R)-(6-((3-fluoro-4-methylphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.70 min, m+H=552.9; 1H NMR (400 MHz,CDCl₃): δ 8.04 (1H, d, J=3.1 Hz), 7.67 (1H, d, J=3.1 Hz), 7.43-7.38 (3H,m), 7.34-7.26 (3H, m), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.2 Hz), 5.50(1H, dd, J=12.4, 2.2 Hz), 4.21 (1H, d, J=16.8 Hz), 3.87 (1H, ddt, J=8.5,4.3, 1.9 Hz), 2.93-2.83 (2H, m), 2.74 (1H, d, J=12.4 Hz), 2.54-2.48 (2H,m), 2.32 (3H, d, J=1.8 Hz).

Example 12D.(R)-(1-(4-fluorophenyl)-6-(phenylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.54 min, m+H=521.2; 1H NMR (400 MHz,CDCl₃): δ 8.05 (1H, d, J=3.1 Hz), 7.74-7.71 (2H, m), 7.67 (1H, d, J=3.1Hz), 7.59-7.55 (1H, m), 7.51-7.47 (2H, m), 7.45-7.40 (2H, m), 7.29 (1H,s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.5 Hz), 5.53 (1H, dd, J=12.3, 2.2Hz), 4.22 (1H, d, J=16.7 Hz), 3.91-3.85 (1H, m), 2.93-2.84 (2H, m), 2.70(1H, d, J=12.4 Hz), 2.53-2.43 (2H, m).

Example 12E.(R)-(6-((3-chlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.71 min, m+H=555.2; 1H NMR (400 MHz,CDCl₃): δ 8.05 (1H, d, J=3.2 Hz), 7.69-7.67 (2H, m), 7.61-7.58 (1H, m),7.54-7.51 (1H, m), 7.45-7.40 (3H, m), 7.30 (1H, s), 7.20-7.14 (2H, m),6.53 (1H, d, J=2.5 Hz), 5.52 (1H, dd, J=12.6, 1.5 Hz), 4.21 (1H, d,J=16.8 Hz), 3.91-3.87 (1H, m), 2.93-2.83 (2H, m), 2.78 (1H, d, J=12.4Hz), 2.58-2.52 (2H, m).

Example 12F.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.77 min, m+H=543.2; 1H NMR (400 MHz,CDCl₃): δ 8.46 (1H, m), 7.82 (1H, d, J=8.0 Hz), 7.61 (1H, ddd, J=8.0,2.3, 0.9 Hz), 7.51-7.48 (2H, m), 7.45-7.40 (2H, m), 7.35-7.33 (2H, m),7.27 (1H, s), 7.18-7.12 (2H, m), 6.46 (1H, d, J=2.1 Hz), 5.57 (1H, dd,J=12.2, 2.1 Hz), 4.29 (1H, d, J=16.9 Hz), 3.84-3.79 (1H, m), 2.90-2.78(2H, m), 2.70 (1H, d, J=12.0 Hz), 2.48-2.39 (8H, m).

Example 12G.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.75 min, m+H=543.2; 1H NMR (400 MHz,CDCl₃): δ 8.50 (1H, dd, J=3.9, 0.4 Hz), 7.71 (1H, m), 7.51-7.48 (2H, m),7.45-7.40 (2H, m), 7.35-7.33 (2H, m), 7.28-7.26 (2H, m), 7.18-7.12 (2H,m), 6.46 (1H, d, J=2.1 Hz), 5.53 (1H, dd, J=12.2, 2.1 Hz), 4.30 (1H, d,J=16.9 Hz), 3.84-3.80 (1H, m), 2.90-2.77 (2H, m), 2.69 (1H, d, J=12.3Hz), 2.48-2.42 (2H, m), 2.40 (3H, s), 2.39 (3H, s).

Example 12H.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(6-methylpyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.77 min, m+H=543.0; 1H NMR (400 MHz,CDCl₃): δ 7.72-7.68 (2H, m), 7.42-7.36 (4H, m), 7.34-7.30 (4H, m),7.18-7.13 (2H, m), 6.45 (1H, d, J=2.0 Hz), 5.55 (1H, dd, J=12.2, 2.0Hz), 4.19 (1H, d, J=17.0 Hz), 3.84-3.80 (1H, m), 2.87 (1H, d, J=17.0Hz), 2.83-2.73 (1H, m), 2.71 (1H, d, J=12.2 Hz), 2.62 (3H, s), 2.54-2.42(2H, m), 2.39 (3H, s).

Example 12I.(R)-(6-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.77 min, m+H=606.9; 1H NMR (400 MHz,CDCl₃): δ 8.00 (1H, d, J=3.0 Hz), 7.98 (1H, dd, J=6.4, 2.3 Hz), 7.90(1H, ddd, J=8.5, 4.3, 2.3 Hz), 7.68 (1H, d, J=3.1 Hz), 7.47-7.40 (2H,m), 7.29 (1H, s), 7.27-7.25 (1H, m), 7.20-7.14 (2H, m), 6.55 (1H, d,J=2.1 Hz), 5.49 (1H, dd, J=12.5, 2.1 Hz), 4.18 (1H, d, J=16.8 Hz), 3.94(1H, ddd, J=8.9, 5.1, 2.1 Hz), 2.93-2.84 (3H, m), 2.66-2.55 (2H, m).

Example 12J.(R)-(1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.75 min, m+H=575.1; 1H NMR (400 MHz,CDCl₃): δ 8.04 (1H, d, J=3.0 Hz), 7.70 (1H, d, J=3.0 Hz), 7.47-7.41 (2H,m), 7.37-7.34 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, d,J=2.1 Hz), 5.49 (1H, dd, J=12.5, 2.0 Hz), 4.20 (1H, d, J=16.8 Hz),3.93-3.88 (1H, m), 2.92-2.83 (3H, m), 2.67-2.55 (2H, m).

Example 12K.(R)-(6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.94 min, m+H=607.1; 1H NMR (400 MHz,CDCl₃): δ 8.02 (1H, d, J=3.0 Hz), 7.73-7.69 (1H, m), 7.68 (1H, d, J=3.0Hz), 7.59 (1H, br d, J=8.2 Hz), 7.53 (1H, br d, J=9.4 Hz), 7.45-7.40(2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, d, J=2.2 Hz), 5.52(1H, dd, J=12.4, 2.0 Hz), 4.20 (1H, d, J=16.9 Hz), 3.96-3.92 (1H, m),2.93-2.84 (3H, m), 2.67-2.62 (1H, m), 2.59-2.55 (1H, m).

Example 12L.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.83 min, m+H=603; 1H NMR (400 MHz, CDCl₃):δ 7.98 (1H, s), 7.91 (1H, br. d, J=7.9 Hz), 7.84-7.80 (1H, m), 7.68-7.61(2H, m), 7.46-7.39 (2H, m), 7.29 (1H, s), 7.20-7.12 (2H, m), 6.51 (1H,d, J=2.1 Hz), 5.54 (1H, dd, J=12.4, 2.1 Hz), 4.17 (1H, d, J=16.7 Hz),3.93-3.89 (1H, m), 2.95-2.77 (3H, m), 2.60-2.49 (5H, m).

Example 12M.(R)-(1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.80 min, m+H=603.0; 1H NMR (400 MHz,CDCl₃): δ 7.96 (1H, s), 7.88 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=7.9 Hz),7.62 (1H, t, J=7.9 Hz), 7.42 (2H, ddt, J=8.1, 5.6, 2.8 Hz), 7.30 (1H,s), 7.21 (1H, d, J=0.9 Hz), 7.20-7.12 (2H, m), 6.52 (1H, d, J=2.2 Hz),5.56 (1H, dd, J=12.4, 2.2 Hz), 4.18 (1H, d, J=16.8 Hz), 3.95-3.88 (1H,m), 2.91-2.80 (3H, m), 2.63-2.50 (5H, m).

Example 12N.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 3.34 min, m+H=589.1; 1H NMR (400 MHz,CDCl₃): δ 8.00 (1H, d, J=3.0 Hz), 7.77 (1H, dd, J=1.8, 0.9 Hz), 7.67(1H, d, J=3.0 Hz), 7.54-7.48 (2H, m), 7.45-7.40 (2H, m), 7.29 (1H, s),7.20-7.14 (2H, m), 6.54 (1H, d, J=2.1 Hz), 5.46 (1H, dd, J=12.6, 2.0Hz), 4.18 (1H, d, J=16.9 Hz), 3.94-3.90 (1H, m), 2.92-2.84 (3H, m),2.66-2.54 (2H, m).

Example 12O.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.92 min, m+H=603.9; 1H NMR (400 MHz,CDCl₃): δ 7.77 (1H, d, J=1.9 Hz), 7.60 (1H, d, J=1.0 Hz), 7.56-7.48 (2H,m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.21-7.13 (2H, m), 6.53 (1H, d,J=2.1 Hz), 5.45 (1H, dd, J=12.5, 2.1 Hz), 4.13 (1H, d, J=16.6 Hz), 3.94(1H, ddt, J=8.5, 3.9, 2.0 Hz), 2.93-2.84 (3H, m), 2.68-2.61 (1H, m),2.57 (3H, d, J=1.0 Hz), 2.58-2.52 (1H, m).

Example 12P.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.62 min, m+H=556.9; 1H NMR (400 MHz,CDCl₃): δ 8.02 (1H, d, J=3.1 Hz), 7.68 (1H, d, J=3.1 Hz), 7.55-7.47 (2H,m), 7.45-7.40 (2H, m), 7.29 (1H, s), 7.27-7.21 (1H, m), 7.20-7.13 (2H,m), 6.54 (1H, d, J=2.2 Hz), 5.47 (1H, dd, J=12.4, 2.0 Hz), 4.19 (1H, d,J=16.8 Hz), 3.93-3.86 (1H, m), 2.93-2.79 (3H, m), 2.63-2.52 (2H, m).

Example 120.(R)-(6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.67 min, m+H=571.1; 1H NMR (400 MHz,CDCl₃): δ 7.63 (1H, m), 7.54-7.49 (2H, m), 7.45-7.40 (2H, m), 7.29 (1H,s), 7.27-7.21 (1H, m), 7.19-7.13 (2H, m), 6.52 (1H, d, J=2.0 Hz), 5.44(1H, dd, J=12.4, 2.0 Hz), 4.15 (1H, d, J=16.9 Hz), 3.93-3.89 (1H, m),2.91-2.80 (3H, m), 2.64-2.52 (5H, m).

Example 12R.(R)-(6-((4-chloro-3-fluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

Using tetrahydrofuran as the reaction solvent in place of diethyl ether.LCMS (Method F, ES-API): RT 2.78 min, m+H=587.1; 1H NMR (400 MHz,CDCl₃): δ 7.62 (1H, m), 7.50-7.40 (5H, m), 7.28 (1H, s), 7.19-7.13 (2H,m), 6.52 (1H, d, J=2.0 Hz), 5.45 (1H, dd, J=12.4, 2.0 Hz), 4.14 (1H, d,J=16.9 Hz), 3.94-3.90 (1H, m), 2.91-2.82 (3H, m), 2.67-2.53 (5H, m).

Example 12S.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.27 min, m+H=539.2; 1H NMR (400 MHz,CDCl₃): δ 7.71 (1H, m), 7.46-7.41 (2H, m), 7.39 (1H, d, J=2.3 Hz), 7.30(1H, s), 7.19-7.13 (2H, m), 6.60 (1H, d, J=2.3 Hz), 6.52 (1H, d, J=2.0Hz), 5.59 (1H, dd, J=12.5, 1.9 Hz), 4.22 (1H, d, J=16.9 Hz), 3.96 (3H,s), 3.92-3.88 (1H, m), 2.94-2.86 (3H, m), 2.69-2.62 (1H, m), 2.55 (3H,d, J=0.9 Hz), 2.52-2.48 (1H, m).

Example 12T.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.25 min, m+H=539.0; 1H NMR (400 MHz,CDCl₃): δ 7.72-7.65 (3H, m), 7.43 (2H, ddt, J=8.2, 5.6, 2.8 Hz), 7.30(1H, s), 7.20-7.13 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.48 (1H, dd,J=12.1, 2.0 Hz), 4.19 (1H, d, J=16.7 Hz), 3.93 (3H, s), 3.84-3.79 (1H,m), 2.95-2.83 (2H, m), 2.68 (1H, d, J=12.1 Hz), 2.56-2.43 (5H, m).

Example 12U.(R)-(6-((1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

Using tetrahydrofuran as the reaction solvent in place of diethyl ether.LCMS (Method F, ES-API): RT 2.46 min, m+H=553.2; 1H NMR (400 MHz,CDCl₃): δ 7.61-7.60 (1H, m), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.20-7.14(2H, m), 6.55 (1H, d, J=2.0 Hz), 6.46 (1H, s), 5.42 (1H, dd, J=12.5, 2.0Hz), 4.20 (1H, d, J=16.9 Hz), 3.96-3.92 (1H, m), 3.84 (3H, s), 3.01 (1H,d, J=12.7 Hz), 2.92-2.76 (3H, m), 2.61-2.56 (4H, m), 2.20 (3H, s).

Example 12V.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(5-methylthiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.40 min, m+H=539.2; 1H NMR (400 MHz,CDCl₃): δ 7.61 (1H, m), 7.46-7.41 (2H, m), 7.35 (1H, d, J=2.0 Hz), 7.29(1H, s), 7.20-7.14 (2H, m), 6.68 (1H, d, J=2.0 Hz), 6.55 (1H, d, J=1.9Hz), 5.45 (1H, dd, J=12.5, 2.0 Hz), 4.20 (1H, d, J=16.9 Hz), 3.97-3.93(4H, m), 3.02 (1H, d, J=12.7 Hz), 2.92-2.76 (3H, m), 2.61-2.55 (4H, m).

Example 12W.(R)-(6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.40 min, m+H=539.1; 1H NMR (400 MHz,CDCl₃): δ 7.98 (1H, d, J=3.1 Hz), 7.65 (1H, d, J=3.1 Hz), 7.47-7.41 (2H,m), 7.39 (1H, d, J=2.0 Hz), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.64 (1H,d, J=2.0 Hz), 6.57 (1H, d, J=1.8 Hz), 5.48 (1H, dd, J=12.7, 2.1 Hz),4.33-4.16 (3H, m), 3.96-3.91 (1H, m), 3.04 (1H, d, J=12.7 Hz), 2.92-2.77(3H, m), 2.62-2.58 (1H, m), 1.40 (3H, t, J=7.2 Hz).

Example 12X.(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.24 min, m+H=539.1; 1H NMR (400 MHz,CDCl₃): δ 8.06 (1H, d, J=3.1 Hz), 7.73 (1H, s), 7.68-7.67 (2H, m),7.46-7.41 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.53 (1H, d, J=2.2Hz), 5.49 (1H, dd, J=12.2, 2.0 Hz), 4.23 (1H, d, J=16.9 Hz), 4.19 (2H,q, J=7.3 Hz), 3.85-3.80 (1H, m), 2.95-2.86 (2H, m), 2.70 (1H, d, J=12.2Hz), 2.55-2.44 (2H, m), 1.52 (3H, t, J=7.3 Hz).

Example 12Y.(R)-(1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.45 min, m+H=553; 1H NMR (400 MHz, CDCl₃):δ 8.07 (d, J=3.1 Hz, 1H), 7.72 (d, J=0.7 Hz, 1H), 7.70-7.65 (m, 2H),7.49-7.39 (m, 2H), 7.31 (s, 1H), 7.22-7.11 (m, 2H), 6.54 (d, J=2.3 Hz,1H), 5.50 (dd, J=12.1, 2.1 Hz, 1H), 4.23 (d, J=16.8 Hz, 1H), 4.09 (t,J=7.1 Hz, 2H), 3.87-3.78 (m, 1H), 2.97-2.84 (m, 2H), 2.68 (d, J=12.2 Hz,1H), 2.57-2.39 (m, 2H), 1.91 (sext., J=7.3 Hz, 2H), 0.92 (t, J=7.4 Hz,3H).

Example 12Z

Isomer A (R)-(1-(4-fluorophenyl)-6- ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Isomer B (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Isomer C (R)-(1-(4-fluorophenyl)-6- ((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Prepared from Intermediate 94. LCMS (Method F, ES-API): RT 2.26 min,m+H=526.1; 1H NMR (400 MHz, CDCl₃): δ 8.07 (1H, d, J=3.1 Hz), 7.81 (1H,s), 7.67 (1H, d, J=3.1 Hz), 7.47-7.42 (2H, m), 7.31 (1H, s), 7.20-7.14(2H, m), 6.56 (1H, d, J=2.1 Hz), 5.63 (1H, dd, J=12.6, 2.1 Hz), 4.25(3H, s), 4.24 (1H, d, J=16.9 Hz), 3.97-3.93 (1H, m), 2.99 (1H, d, J=12.7Hz), 2.99-2.86 (2H, m), 2.77-2.70 (1H, m), 2.57-2.52 (1H, m).

Example 12AA

Isomer A (R)-(1-(4-fluorophenyl)-6- ((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Isomer B (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Isomer C (R)-(1-(4-fluorophenyl)-6- ((1-propyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8- hexahydro-1H- pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2- yl)methanone

Prepared from Intermediate 95. LCMS (Method F, ES-API): RT 2.54 min,m+H=554.2; 1H NMR (400 MHz, CDCl₃): δ 8.08 (1H, d, J=3.1 Hz), 7.82 (1H,s), 7.68 (1H, d, J=3.1 Hz), 7.47-7.42 (2H, m), 7.31 (1H, s), 7.20-7.14(2H, m), 6.55 (1H, d, J=2.2 Hz), 5.64 (1H, dd, J=12.6, 2.0 Hz), 4.43(2H, t, J=7.1 Hz), 4.25 (1H, d, J=16.9 Hz), 3.97-3.92 (1H, m), 2.96 (1H,d, J=12.9 Hz), 2.94-2.86 (2H, m), 2.74-2.67 (1H, m), 2.56-2.52 (1H, m),2.01 (2H, sext, J=7.1 Hz), 0.94 (3H, t, J=7.1 Hz).

Example 13.(R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone

1-Methyl-1H-imidazole (104 mg, 1.267 mmol) in dry ether (5 mL) was addedto butyllithium (2.5M in hexanes) (519 μl, 1.298 mmol) in dry ether (2mL) at −78° C. The reaction mixture was stirred at −78° C. for 45minutes. A solution of (R)-methyl1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(200 mg, 0.415 mmol) in dry ether (5 mL) was added dropwise and thereaction mixture was stirred for 45 minutes at −78° C., then allowed towarm to room temperature over 2 hours. Water (20 mL) was added and thereaction mixture was stirred at room temperature for 10 minutes. Theaqueous phase was extracted with ethyl acetate (3×20 mL), the combinedorganic phases were washed with brine (20 mL), dried (magnesiumsulfate), and solvent removed to give a yellow oil. The crude productwas purified by chromatography on silica gel (gradient: 0-60% ethylacetate in isohexane) to afford(R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone(22 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.52 min,m+H=532.0; 1H NMR (400 MHz, CDCl₃): δ 7.61-7.58 (2H, m), 7.46-7.40 (2H,m), 7.31 (1H, s), 7.29-7.27 (2H, m), 7.18 (1H, d, J=0.9 Hz), 7.17-7.12(2H, m), 6.99 (1H, br. s), 6.50 (1H, d, J=2.2 Hz), 5.53 (1H, dd, J=12.2,2.2 Hz), 4.45 (1H, d, J=16.7 Hz), 3.88-3.84 (4H, m), 2.92-2.78 (2H, m),2.60 (1H, d, J=12.2 Hz), 2.50-2.37 (5H, m).

The following examples were similarly prepared from the appropriatestarting materials:

Example 13A.(R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone

LCMS (Method F, ES-API): RT 2.52 min, m+H=532.2; 1H NMR (400 MHz,CDCl₃): δ 7.52-7.49 (2H, m), 7.46-7.36 (4H, m), 7.32 (1H, s), 7.20 (1H,d, J=0.9 Hz), 7.18-7.12 (2H, m), 7.00 (1H, d, J=0.4 Hz), 6.51 (1H, d,J=2.2 Hz), 5.55 (1H, dd, J=12.2, 2.1 Hz), 4.46 (1H, d, J=16.7 Hz),3.89-3.85 (4H, m), 2.91-2.80 (2H, m), 2.62 (1H, d, J=12.4 Hz), 2.51-2.40(5H, m).

Example 14.(R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide

2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate Methanaminium (HATU) (42.7 mg, 0.112 mmol) was addedto a solution of(R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzoicacid (57 mg, 0.102 mmol), dimethylamine (51.0 μl, 0.102 mmol) andtriethylamine (28.4 μl, 0.204 mmol) in dichloromethane (3 mL). Theresultant mixture was stirred at room temperature for 1 hour. Thereaction was diluted with dichloromethane (5 mL) and washed with asaturated solution of sodium hydrogen carbonate (aqueous, 5 mL). Theorganic phase was passed through a phase separator and solvent removedto give a yellow solid. The crude product was purified by chromatographyon silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford(R)-3-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-N,N-dimethylbenzamide(7 mg) as a white solid. LCMS (Method F, ES-API): RT 2.24 min,m+H=586.1; 1H NMR (400 MHz, CDCl₃): δ 8.68 (1H, ddd, J=4.7, 1.7, 0.9Hz), 7.90 (1H, dt, J=7.9, 1.2 Hz), 7.84 (1H, td, J=7.7, 1.7 Hz),7.74-7.71 (2H, m), 7.61 (1H, dt, J=7.7, 1.4 Hz), 7.57-7.39 (4H, m), 7.28(1H, s), 7.20-7.13 (2H, m), 6.47 (1H, d, J=2.0 Hz), 5.52 (1H, dd,J=12.1, 2.0 Hz), 4.27 (1H, d, J=16.9 Hz), 3.86-3.77 (1H, m), 3.14 (3H,s), 2.94-2.76 (5H, m), 2.70 (1H, d, J=12.1 Hz), 2.50-2.43 (2H, m).

Example 15.(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

2-Bromo-4-(trifluoromethyl)pyridine (171 μl, 1.382 mmol) in drytetrahydrofuran (1 mL) was added to butyllithium (2.5 M in Hexanes) (885μl, 1.416 mmol) in dry tetrahydrofuran (2 mL) at −78° C. The reactionmixture was stirred at −78° C. for 45 minutes, then a solution of(R)-methyl6-((l-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(220 mg, 0.453 mmol) in dry tetrahydrofuran (2 mL) was added dropwiseand the reaction mixture stirred for 1 hour at −78° C. Water (10 mL) wasadded and the reaction mixture was stirred at room temperature for 10minutes. The aqueous phase was extracted with ethyl acetate (2×15 mL),and the combined organic layers were washed with brine (20 mL), driedover magnesium sulfate, filtered and concentrated in vacuo to give anorange oil. The crude product was purified by chromatography on silicagel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC(Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 35-70% acetonitrile in water) to afford(R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone(23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min,m+H=601.2; 1H NMR (400 MHz, CDCl₃): δ 8.88-8.87 (1H, m), 8.15 (1H, m),7.71-7.69 (2H, m), 7.67 (1H, d, J=0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H,s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.0, 2.0Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, J=16.9 Hz),2.88-2.79 (1H, m), 2.67 (1H, d, J=12.3 Hz), 2.52-2.40 (2H, m), 1.51 (3H,t, J=7.3 Hz).

The following examples were similarly prepared from appropriateintermediates:

Example 15A.(R)-pyridin-2-yl(1-(pyridin-3-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)methanone

LCMS (Method F, ES-API): RT 2.33 min, m+H=566.0; 1H NMR (400 MHz,CDCl₃): δ 8.78-8.76 (1H, m), 8.66 (1H, ddd, J=4.7, 1.6, 0.9 Hz), 8.61(1H, dd, J=4.7, 1.6 Hz), 7.94 (1H, s), 7.90-7.79 (5H, m), 7.62 (1H, t,J=7.9 Hz), 7.48 (1H, ddd, J=8.8, 6.2, 1.5 Hz), 7.44 (1H, ddd, J=8.8,4.8, 0.7 Hz), 7.36 (1H, s), 6.56 (1H, d, J=2.0 Hz), 5.57 (1H, dd,J=12.3, 2.0 Hz), 4.30 (1H, d, J=17.0 Hz), 3.92-3.85 (1H, m), 2.93-2.78(3H, m), 2.62-2.50 (2H, m).

Example 15B.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-phenyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

Quenching the reaction with acetic acid in place of water. LCMS (MethodF, ES-API): RT 2.83 min, m+H=565.0; 1H NMR (400 MHz, CDCl₃): δ 8.62-8.60(1H, m), 7.88-7.81 (2H, m), 7.74 (1H, dd, J=1.8, 0.4 Hz), 7.52-7.44 (7H,m), 7.38-7.34 (1H, m), 7.29 (1H, s), 6.57 (1H, d, J=2.1 Hz), 5.54 (1H,dd, J=12.3, 1.9 Hz), 4.26 (1H, d, J=16.8 Hz), 3.91-3.85 (1H, m),2.92-2.75 (3H, m), 2.64-2.49 (2H, m).

Example 15C.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(3,4-difluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

Quenching the reaction with acetic acid in place of water. LCMS (MethodF, ES-API): RT 2.93 min, m+H=600.9; 1H NMR (400 MHz, CDCl₃): δ 8.59 (1H,dt, J=4.7, 1.4 Hz), 7.86-7.79 (2H, m), 7.73 (1H, d, J=1.9 Hz), 7.52-7.43(3H, m), 7.34 (1H, ddd, J=10.7, 6.9, 2.5 Hz), 7.29-7.24 (2H, m),7.22-7.18 (1H, m), 6.51 (1H, d, J=2.2 Hz), 5.50 (1H, d, J=12.5 Hz), 4.23(1H, d, J=16.9 Hz), 3.90-3.84 (1H, m), 2.93-2.80 (3H, m), 2.64 (1H, td,J=11.7, 3.4 Hz), 2.53 (1H, dt, J=14.8, 2.3 Hz).

Example 15D.(R)-(6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS (Method F, ES-API): RT 2.65 min, m+H=581.2; 1H NMR (400 MHz,DMSO-d6): δ 8.72 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 8.00 (1H, dt, J=7.7, 1.7Hz), 7.76 (1H, dt, 7.7, 0.9 Hz), 7.66 (1H, ddd, J=7.7, 4.7, 1.2 Hz),7.51-7.47 (2H, m), 7.44-7.42 (2H, m), 7.40-7.36 (3H, m), 6.65 (1H, s),5.30 (1H, dd, J=12.5, 1.7 Hz), 4.09 (1H, d, J=16.9 Hz), 4.04 (3H, m),3.75-3.73 (1H, m), 2.97-2.90 (2H, m), 2.64-2.54 (3H, m).

Example 16.(R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(30 mg, 0.055 mmol) was dissolved in a solution of dimethylamine intetrahydrofuran (2M, 545 μl, 1.091 mmol), and the reaction mixturestirred at room temperature overnight. The solvent was removed in vacuoto give a yellow oil, which was purified by chromatography on silica gel(gradient: 10-100% ethyl acetate in isohexane) to afford(R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(25 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.38 min,m+H=559.3; 1H NMR (400 MHz, CDCl₃): δ 8.62 (1H, ddd, J=4.8, 1.8, 0.9Hz), 8.43 (1H, d, J=2.5 Hz), 7.88 (1H, dt, J=8.0, 1.1 Hz), 7.81 (1H, td,J=7.7, 1.8 Hz), 7.60 (1H, dd, J=9.1, 2.5 Hz), 7.46-7.40 (3H, m), 7.28(1H, s), 7.20-7.12 (2H, m), 6.47 (1H, d, J=2.2 Hz), 6.39 (1H, dd, J=9.1,0.8 Hz), 5.47 (1H, dd, J=12.0, 2.2 Hz), 4.29 (1H, d, J=16.9 Hz),3.84-3.79 (1H, m), 3.14 (6H, s), 2.92-2.75 (2H, m), 2.70 (1H, d, J=12.0Hz), 2.51-2.44 (2H, m).

Example 17.(R)-5-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylpyridin-2(1H)-one

1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid, ammonium salt (1 g,4.85 mmol) was suspended in N,N-dimethylformamide (8 ml), and thionylchloride (2.1 ml) was added. The reaction mixture was stirred at roomtemperature for 3 hours, giving a clear brown solution, beforeevaporation in vacuo to give crude sulphonyl chloride as a pale brownviscous oil. (R)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(0.2 g, 0.421 mmol) was dissolved in HCl (4M in dioxane) (2.107 ml, 8.43mmol), and the reaction mixture stirred at room temperature for 45minutes, then evaporated to give a yellow solid. This intermediate wasdissolved in dichloromethane (8 mL) and triethylamine (1.175 ml, 8.43mmol), and 25% of the crude sulphonyl chloride added. The reactionmixture was stirred at room temperature for 72 hours, then diluted withdichloromethane (100 ml) and washed with 2M hydrochloric acid (2×50 ml),and the organic phase dried (magnesium sulfate), filtered and evaporatedto give a brown gum. The crude product was purified first bychromatography on silica gel (gradient: 50-100% ethyl acetate inisohexane), followed by preparative HPLC (Gilson, Acidic (0.1% Formicacid), Agilent Prep C-18, 5 μm, 21.2×50 mm column, 25-40% acetonitrilein water) to afford(R)-5-((1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)-1-methylpyridin-2(1H)-one(5 mg) as a white solid. LCMS (Method F, ES-API): RT 2.08 min,m+H=546.2; 1H NMR (400 MHz, CDCl₃): δ 8.56 (1H, d, J=3.3 Hz), 7.88-7.79(3H, m), 7.50-7.40 (3H, m), 7.33 (1H, d, J=9.2 Hz), 7.29-7.27 (1H, m),7.17 (2H, t, J=8.3 Hz), 6.52 (1H, s), 6.35 (1H, d, J=9.6 Hz), 5.52 (1H,d, J=12.5 Hz), 4.23 (1H, d, J=16.7 Hz), 3.91-3.84 (1H, m), 3.51 (3H, s),3.02-2.70 (4H, m), 2.55 (1H, d, J=14.4 Hz).

Example 18.(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

HCl/Dioxane (4M) (25.3 ml, 101 mmol) was added to (R)-tert-butyl1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(2.75 g, 5.07 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. The solvent was removed in vacuo to give an orangegum. This was dissolved in dichloromethane (75 mL) and Hunig's base(4.43 ml, 25.3 mmol) was added followed by1-methyl-1H-pyrazole-4-sulfonyl chloride (1.099 g, 6.08 mmol). Thereaction mixture was stirred at room temperature for 1 h. The solventwas removed in vacuo to give an orange oil. The crude product waspurified twice by chromatography on silica gel (gradient: 0-70% ethylacetate in isohexane, followed by 0-60% ethyl acetate indichloromethane), to give(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone(1.89 g) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.39 min,m+H=587.2. 1H NMR (400 MHz, CDCl₃): δ 8.87 (1H, d, J=5.0 Hz), 8.16-8.15(1H, m), 7.72-7.70 (1H, m), 7.69-7.66 (2H, m), 7.47-7.42 (2H, m), 7.30(1H, s), 7.21-7.14 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.44 (1H, dd,J=12.0, 2.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.93 (3H, s), 3.80-3.76 (1H,m), 2.94 (1H, J=16.9 Hz), 2.88-2.79 (1H, m), 2.66 (1H, d, J=12.1 Hz),2.53-2.48 (1H, m), 2.43 (1H, ddd, J=12.6, 10.5, 3.5 Hz).

Example 19.(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

To HCl 2M in ether (2809 μl, 5.62 mmol) was added (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(135 mg, 0.281 mmol) as a solution in ether (1 mL). The resultingsuspension was stirred at room temperature for 1 h. The solvent wasremoved to give a white solid. This was dissolved in dichloromethane(1.4 mL) and Hunig's base (245 μl, 1.405 mmol), and3,4-dichlorobenzene-1-sulfonyl chloride (76 mg, 0.309 mmol) was added tothe solution. The resulting solution was stirred at room temperature for18 h. The crude product was purified by chromatography on silica gel(gradient: 5-95% ethyl acetate in isohexane to afford(R)-(6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone(111 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.76 min,m+H=588.8; 1H NMR (400 MHz, CDCl₃): δ 8.85 (1H, d, J=2.2 Hz), 8.22 (1H,d, J=2.2 Hz), 7.77 (1H, t, J=1.2 Hz), 7.52 (2H, d, J=1.2 Hz), 7.45-7.40(2H, m), 7.28 (1H, s), 7.20-7.13 (2H, m), 6.52 (1H, d, J=2.2 Hz), 5.44(1H, dd, J=12.6, 2.2 Hz), 4.13 (1H, d, J=16.8 Hz), 3.90-3.87 (1H, m),2.92-2.81 (2H, m), 2.78 (1H, d, J=12.6 Hz), 2.62-2.50 (2H, m).

Example 20. Human Glucocorticoid Receptor (GR) Fluorescence Polarisation(FP) Binding Assay

The following is a description of a FP assay for measuring compoundinhibition of labelled glucocorticoid binding to the human recombinantGR.

The binding affinity of test compounds was determined using a FP bindingassay using human recombinant GR (PanVera P2812) and a fluorescentlabelled glucocorticoid ligand (Fluorome GS Red) (PanVera P2894). Thepresence of inhibitors prevents the formation of a GS Red/GR complexresulting in a decrease in the measured polarisation value. The changein polarisation value in the presence of test compounds is used tocalculate the binding affinity of the compound for GR.

This assay was performed in 384 well, black, round-bottom, polypropylenemicro titre plates in a final volume of 20 μl. The assay contained 5 μlnM GR (final concentration), 5 μl 0.5 nM Fluorome GS Red (finalconcentration) in the presence of 10 μl test compounds. Positive controlwells (high polarisation) receive, 10 μl % (v:v) DMSO vehicle (1% (v/v)final concentration)+5 μl 1 nM GR and 5 μl 0.5 nM Fluorome GS Red.Negative control wells (low polarisation) receive 10 μl 2 μMdexamethasone (1 μM final concentration)+5 μl 1 nM GR and 5 μl 0.5 nMFluorome GS Red. Assay blank background wells (used for normalisation)receive 15 μl 1× GS screening buffer+5 μl GR.

For the IC₅₀ determination (concentration of compound that displaces 50%of the bound GS Red), compounds were tested at eight differentconcentrations in duplicate in two independently performed experiments.Compounds were prepared as solubilised solids at 10 mM in DMSO. On theday of assay, an 8 point half-log serial dilution (S5 μl DMSO+25 μlcompound solution) was prepared. A 1:50 dilution (1 μl compoundsolution+49 μl 1× GR screening buffer) was prepared for each compound.The compounds were prepared at 2× final assay concentration.

The reagents were added to the 384 well micro titre plates in thefollowing order: 10 μl test compound/vehicle/1 μM dexamethasone, 5 μlFluorome GS Red and 5 μl GR. The plates were mixed and incubated for 4hour at room temperature. FP was measured using an Envision Excite platereader with 535 nm excitation and 590 nm emission interference filters.

Milli-polarisation (mP) values were calculated using the below equation:mP=1000*(S−G*P)/(S+G*P)where S and P are assay blank background subtracted fluorescence units,G=G-factor (1.07).

Compound IC₅₀ values were calculated by plotting a [compound] v. %inhibition curve and fitting the data to a 4-parameter logistic fitequation. Compound K_(i) (equilibrium dissociation constant) values weredetermined from the experimental ICso values using a ligand depletioncorrection equation (see below) assuming the antagonists werecompetitive inhibitors with respect to dexamethasone (PharmacologicAnalysis of Drug Receptor Interactions, 2^(nd) Ed., p 385-410, 1993,Raven Press, New York).

$K_{i} = \frac{( L_{b} )*( {IC}_{50} )*( K_{d} )}{{( L_{o} )*( R_{o} )} + {L_{B}*( {R_{o} - L_{o} + L_{b} - K_{d}} )}}$

Equilibrium dissociation constant of GS red ligand (K_(d)) 0.3 nM Boundtracer concentration (L_(b)) 0.3 nM Total tracer concentration (L_(o))0.5 nM Total receptor concentration (R_(o)) 1.0 nMReagents:

10× GR screening buffer (100 mM potassium phosphate pH 7.4, 200 mMNa₂MoO₄, 1 mM EDTA, 20% (v/v) DMSO). To prepare 1× GR screening buffer,combine lml 10× GR screening buffer (PanVera P2814)+1 ml stabilisingpeptide (PanVera P2815)+7.95 ml 4° C. MQ water. Add 50 μl 1M DTT, vortexand place on ice until use.

Example 21. HepG2 Tyrosine Aminotransferase (TAT) Assay

Glucocorticoid mediated activation of TAT occurs by transactivation ofglucocorticoid response elements in the TAT promoter by glucocorticoidreceptor-agonist complex. The following protocol describes an assay formeasuring induction of TAT by dexamethasone in HepG2 cells (a humanliver hepatocellular carcinoma cell line; ECACC, UK).

TAT activity was measured as outlined in the literature by A. Ali etal., J. Med. Chem., 2004, 47, 2441-2452. Dexamethasone induced TATproduction with an average EC₅₀ value (half-maximal effect) of 20 nM.

HepG2 cells were cultured using MEME media supplemented with 10% (v/v)foetal bovine serum; 2 mM L-glutamine and 1% (v/v) NEAA at 37° C.,5%/95% (v/v) CO₂/air. The HepG2 cells were counted and adjusted to yielda density of 0.125×10⁶ cells/ml in RPMI 1640 without phenol red, 10%(v/v) charcoal stripped FBS, 2 mM L-glutamine and seeded at 25,000cells/well in 200 μl into 96 well, sterile, tissue culture micro titreplates, and incubated at 37° C., 5% CO₂ for 24 hours

Growth media was removed and replaced with assay media {RPMI 1640without phenol red, 2 mM L-glutamine+10 μM forskolin}. Test compoundswere screened against a challenge of 100 nM dexamethasone. Compoundswere serially half log diluted in 100% (v/v) dimethylsupfoxide from a 10mM stock. Then an 8-point half-log dilution curve was generated followedby a 1:100 dilution into assay media to give a 10× final assay[compound]: this resulted in final assay [compound] that ranged 10 to0.003 μM in 0.1% (v/v) dimethylsulfoxide.

Test compounds were pre-incubated with cells in micro-titre plates for30 minutes at 37° C., 5/95 (v/v) CO₂/air, before the addition of 100 nMdexamethasone and then subsequently for 20 hours to allow optimal TATinduction.

HepG2 cells were then lysed with 30 μl of cell lysis buffer containing aprotease inhibitor cocktail for 15 minutes at 4° C. 155 μl of substratemixture was then added containing 5.4 mM Tyrosine sodium salt, 10.8 mMalpha ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1M potassiumphosphate buffer (pH 7.4). After 2 hours incubation at 37° C. thereaction was terminated by the addition of 15 μl of 10M aqueouspotassium hydroxide solution, and the plates incubated for a further 30minutes at 37° C. The TAT activity product was measured by absorbance atλ 340 nm.

IC₅₀ values were calculated by plotting % inhibition (normalised to 100nM dexamethasone TAT stimulation) v. [compound] and fitting the data toa 4 parameter logistic equation. IC₅₀ values were converted to Ki(equilibrium dissociation constant) using the Cheng and Prusoffequation, assuming the antagonists were competitive inhibitors withrespect to dexamethasone.

TABLE 1 Activity Data

GR Example R¹ R^(1a) Ring J R² n R³ binding TAT Int. 13 pyridin-2-ylpyridin-3-yl 6-Cl 0 4-F-phenyl Int. 14 thiazol-2-yl pyridin-3-yl 6-Cl 04-F-phenyl 1 pyridin-2-yl phenyl 4-CF₃ 0 4-F-phenyl +++ +++ 1A1H-imidazol- 1-Me phenyl 4-CF₃ 0 4-F-phenyl ++ ++ 2-yl 1B pyridin-3-ylphenyl 4-CF₃ 0 4-F-phenyl ++ + 1C thiazol-2-yl phenyl 4-CF₃ 0 4-F-phenyl+++ +++ 1D 1,3,4- 5-Me phenyl 4-CF₃ 0 4-F-phenyl + + oxadiazol-2- yl 1Eoxazol-4-yl phenyl 4-CF₃ 0 4-F-phenyl +++ ++ 1F oxazol-2-yl phenyl 4-CF₃0 4-F-phenyl +++ ++ 1G furan-2-yl phenyl 4-CF₃ 0 4-F-phenyl +++ ++ 1Hthiophen-2-yl phenyl 4-CF₃ 0 4-F-phenyl +++ ++ 1I oxazol-2-yl phenyl3-Me 0 4-F-phenyl +++ ++ 1J pyrimidin-2- phenyl 3-Me 0 4-F-phenyl +++ ++yl 1K pyridin-2-yl 4-OMe phenyl 3,5-difluoro 0 4-F-phenyl +++ +++ 1Lpyridin-2-yl 4-Et phenyl 3,4,5-trifluoro 0 4-F-phenyl +++ +++ 1Mpyridin-2-yl 4-OMe phenyl 3,4,5-trifluoro 0 4-F-phenyl +++ +++ 2pyridin-2-yl phenyl 4-F 0 4-F-phenyl +++ +++ 2A thiazol-2-yl phenyl 3-F1 4-F-phenyl +++ + 2B thiazol-2-yl tetrahydrofuran- 1 4-F-phenyl ++ +2-yl 2C pyridin-2-yl phenyl 2-Me 0 4-F-phenyl +++ +++ 2D pyridin-2-ylphenyl 4-Et 0 4-F-phenyl +++ +++ 2E pyridin-2-yl phenyl 3-Me 04-F-phenyl +++ +++ 2F pyridin-2-yl phenyl 3-Cl 0 4-F-phenyl +++ +++ 2Gpyridin-2-yl phenyl 3-OMe 0 4-F-phenyl +++ +++ 2H pyridin-2-yl phenyl3-F, 4-Cl 0 4-F-phenyl +++ +++ 2I pyridin-2-yl phenyl 4-OMe 0 4-F-phenyl+++ +++ 2J pyridin-2-yl phenyl 3-F, 4-Me 0 4-F-phenyl +++ +++ 2Kpyridin-2-yl phenyl 0 4-F-phenyl +++ +++ 2L pyridin-2-yl phenyl 2-F 04-F-phenyl +++ +++ 2M pyridin-2-yl 1H-pyrazol-4-yl 1-Me 0 4-F-phenyl +++++ 2N pyridin-2-yl pyridin-3-yl 6-CF₃ 0 4-F-phenyl +++ +++ 2Opyridin-2-yl phenyl 4-Me 0 4-F-phenyl +++ +++ 2P pyridin-2-yl phenyl3-CF₃, 4-F 0 4-F-phenyl ++ +++ 2Q pyridin-2-yl phenyl 4-CN 0 4-F-phenyl+++ ++ 2R pyridin-2-yl pyridin-3-yl 6-OMe 0 4-F-phenyl +++ +++ 2Spyridin-2-yl tetrahydro-2H- 0 4-F-phenyl + + pyran-4-yl 2T pyridin-2-ylcyclohexyl 0 4-F-phenyl + + 2U pyridin-2-yl 4-CF₃ 1H-pyrazol-5-yl 1-Et 04-F-phenyl + +++ 2V pyridin-2-yl 4-CF₃ 1H-pyrazol-4-yl 3,5-dimethyl 04-F-phenyl + ++ 2W pyridin-2-yl 4-CF₃ 1H-imidazol-4-yl 0 4-F-phenyl + ++3 pyridin-2-yl pyridin-3-yl 6-morpholine 0 4-F-phenyl +++ ++ 4thiazol-2-yl pyridin-3-yl 6-pyrrolidin- 0 4-F-phenyl +++ + 1-yl 5thiazol-2-yl phenyl 4-F 0 4-F-phenyl +++ ++ 5A thiazol-2-yl phenyl 3-F 04-F-phenyl +++ +++ 5B thiazol-2-yl phenyl 4-CN 1 4-F-phenyl +++ + 5Cpyridin-2-yl phenyl 3-CF₃ 0 4-F-phenyl +++ +++ 5D 1H-1,2,4- 1-Me phenyl4-CF₃ 0 4-F-phenyl +++ + triazol-5-yl 5E pyrazin-2-yl phenyl 4-CF₃ 04-F-phenyl +++ ++ 5F pyridin-2-yl pyridin-3-yl 5-F 0 4-F-phenyl +++ ++5G pyridin-2-yl phenyl 3-F 0 4-F-phenyl +++ +++ 5H pyridin-2-yl 5-OMephenyl 4-CF₃ 0 4-F-phenyl ++ +++ 5I thiazol-5-yl phenyl 4-CF₃ 04-F-phenyl +++ + 5J thiazol-2-yl pyridin-3-yl 5-F 0 4-F-phenyl 6thiazol-2-yl phenyl 4-pyrrolidin- 0 4-F-phenyl ++ ++ 1-yl 6Athiazol-2-yl phenyl 3-pyrrolidin- 0 4-F-phenyl +++ + 1-yl 7 thiazol-2-ylpyridin-3-yl 5-piperidin-1- 0 4-F-phenyl +++ ++ yl 7A thiazol-2-ylpyridin-3-yl 5-pyrrolidin- 0 4-F-phenyl +++ ++ 1-yl 8 pyridin-2-ylpyridin-3-yl 6-pyrrolidin- 0 4-F-phenyl +++ + 1-yl 9 thiazol-2-ylpyridin-3-yl 6-((R)-3- 0 4-F-phenyl +++ + fluoropyrrolidin- 1-yl) 10pyridin-2-yl phenyl 4-pyrrolidin- 0 4-F-phenyl +++ + 1-yl 10Apyridin-2-yl pyridin-3-yl 5-piperidin-1- 0 4-F-phenyl +++ +++ yl 10Bpyridin-2-yl pyridin-3-yl 5-pyrrolidin- 0 4-F-phenyl +++ +++ 1-yl 11thiazol-4-yl phenyl 4-CF₃ 0 4-F-phenyl +++ ++ 11A pyridin-2-yl phenyl4-Cl 0 4-F-phenyl +++ +++ 11B pyridin-2-yl phenyl 3-Me, 4-OMe 04-F-phenyl +++ +++ 11C pyridin-2-yl phenyl 3-Cl, 4-OMe 0 4-F-phenyl +++++ 11D pyridin-2-yl phenyl 3-F, 4-OMe 0 4-F-phenyl +++ +++ 11Epyridin-2-yl phenyl 2-F, 4-Me 0 4-F-phenyl +++ ++ 11F thiazol-4-ylphenyl 3-Me 0 4-F-phenyl +++ ++ 11G pyridin-2-yl phenyl 3-CN 04-F-phenyl +++ +++ 11H pyridin-2-yl phenyl 4-OCHF₂ 0 4-F-phenyl +++ +++11I pyridin-2-yl phenyl 3-OCF₃ 0 4-F-phenyl +++ +++ 11J pyridin-2-ylphenyl 3,5-difluoro 0 4-F-phenyl +++ +++ 11K thiazol-4-yl phenyl 4-Me 04-F-phenyl +++ +++ 11L pyridin-2-yl phenyl 3-OCHF₂ 0 4-F-phenyl +++ +++11M pyridin-2-yl phenyl 3,4-dimethyl 0 4-F-phenyl +++ +++ 11Npyridin-2-yl phenyl 3,5-dimethyl 0 4-F-phenyl +++ +++ 11O pyridin-2-ylpyridin-2-yl 6-Me 0 4-F-phenyl +++ +++ 11P pyridin-2-yl phenyl3,4-difluoro 0 4-F-phenyl +++ +++ 11Q pyridin-2-yl phenyl3,4,5-trifluoro 0 4-F-phenyl +++ +++ 11R pyridin-2-yl phenyl 3-Cl, 4-F 04-F-phenyl +++ +++ 11S pyridin-2-yl 4-Me phenyl 3-CN 0 4-F-phenyl ++++++ 11T pyridin-2-yl 4-Me 1H-pyrazol-4-yl 1-Me 0 4-F-phenyl +++ +++ 11Upyridin-2-yl 4-Me phenyl 3,4-difluoro 0 4-F-phenyl +++ +++ 11Vpyridin-2-yl 4-Me 1H-imidazol-4-yl 1-Me 0 4-F-phenyl +++ ++ 11Wpyiridn-2-yl 4-Me phenyl 3,5-difluroo 0 4-F-phenyl +++ +++ 11Xpyridin-2-yl 4-Me phenyl 3,4,5-trifluoro 0 4-F-phenyl +++ +++ 11Ypyridin-2-yl phenyl 3-SO₂Me 0 4-F-phenyl +++ ++ 11Z pyridin-2-yl phenyl3-CO2H 0 4-F-phenyl 11AA pyridin-2-yl phenyl 3-CH₂OMe 0 4-F-phenyl +++++ 11AB pyridin-2-yl 4-methyl-1,3,4-dihydro-2H- 0 4-F-phenyl +++ ++pyrido[3,2-b][1,4]oxazin-7-yl 11AC pyridin-2-yl phenyl 2,3,4-trifluoro 04-F-phenyl +++ +++ 11AD pyridin-2-yl pyridin-2-yl 6-CF₃ 0 4-F-phenyl ++++++ 11AE pyridin-2-yl 4-Me pyridin-2-yl 6-CF₃ 0 4-F-phenyl +++ +++ 11AFpyridin-2-yl phenyl 3,4-dichloro 0 4-F-phenyl +++ +++ 11AG pyridin-2-yl4-Me phenyl 3-CF₃ 0 4-F-phenyl +++ +++ 11AH pyridin-2-yl 4-Me1H-pyrazol-4-yl 1-Et 0 4-F-phenyl +++ +++ 11AI pyridin-2-yl 4-Me1H-pyrazol-4-yl 1,5-dimethyl 0 4-F-phenyl +++ +++ 11AJ pyridin-2-yl 4-Me1H-pyrazol-5-yl 1-Me 0 4-F-phenyl +++ +++ 11AK pyridin-2-yl 4-Me1H-pyrazol-3-yl 1-Me 0 4-F-phenyl +++ +++ 11AL pyridin-2-yl 4-Me phenyl3-Me, 4-F 0 4-F-phenyl +++ +++ 11AM pyridin-2-yl 4-Me4-methyl-3,4-dihydro-2H- 0 4-F-phenyl +++ +++pyrido[3,2-b][1,4]oxazin-7-yl 11AN pyridin-2-yl 4-Me2,3-dihydrobenzofuran-5-yl 0 4-F-phenyl +++ +++ 11AO pyridin-2-yl 4-Me1-methylindolin-2-one-5-yl 0 4-F-phenyl +++ +++ 11AP pyridin-2-yl 4-Mephenyl 3-SO₂Me 0 4-F-phenyl +++ +++ 11AQ pyridin-2-yl 4-Me1H-pyrazol-4-yl 1,3-dimethyl 0 4-F-phenyl +++ ++ 11AR pyridin-2-yl 4-Me2,3-dihydrobenzo[b][1,4]dioxin- 0 4-F-phenyl +++ +++ 6-yl 11ASpyridin-2-yl 4-Me phenyl 3-F, 4-CF₃ 0 4-F-phenyl +++ +++ 11ATpyridin-2-yl phenyl 3-F, 4-CF₃ 0 4-F-phenyl +++ +++ 11AU pyridin-2-yl4-Et phenyl 3-CN 0 4-F-phenyl +++ +++ 11AV pyridin-2-yl 4-Etpyridin-2-yl 6-CF₃ 0 4-F-phenyl +++ +++ 11AW pyridin-2-yl 4-Me phenyl3-CO₂H 0 4-F-phenyl +++ + 11AX pyridin-2-yl 4-Me isoxazol-4-yl3,5-dimethyl 0 4-F-phenyl +++ ++ 11AY pyridin-2-yl 1H-pyrazol-4-yl 1-Et0 4-F-phenyl +++ ++ 11AZ pyridin-2-yl phenyl 3-CF₃ 0 phenyl +++ ++ 11BApyridin-2-yl 4-Me 1H-pyrazol-5-yl 1,3-dimethyl 0 4-F-phenyl +++ +++ 11BBpyridin-2-yl 4-Me pyridin-4-yl 2-CF₃ 0 4-F-phenyl +++ +++ 11BCpyridin-2-yl 4-Me pyridin-2-yl 4-CF₃ 0 4-F-phenyl +++ +++ 11BDpyridin-2-yl 4-Me 1H-pyrazol-4-yl 5-Me 0 4-F-phenyl +++ ++ 11BEpyridin-2-yl pyridin-4-yl 2-CF₃ 0 4-F-phenyl +++ ++ 11BF pyridin-2-ylphenyl 3-CF₃, 4-Cl 0 4-F-phenyl +++ ++ 11BG pyridin-2-yl phenyl 3-Cl,4-Me 0 4-F-phenyl +++ +++ 11BH pyridin-4-yl 2- phenyl 3,4-difluoro 04-F-phenyl + + pyrrolidin- phenyl 1-yl 11BI pyridin-2-yl 4-CF₃1H-pyrazol-3-yl 1-Me 0 4-F-phenyl +++ +++ 11BJ pyridin-2-yl1H-pyrazol-3-yl 1-Me 0 4-F-phenyl +++ ++ 11BK pyridin-2-yl 4-CF₃1H-pyrazol-4-yl 5-Me 0 4-F-phenyl +++ +++ 11BL pyridin-2-yl 4-CF₃ phenyl3-CN 0 4-F-phenyl +++ +++ 11BM pyridin-2-yl 4-CF₃ 1H-pyrazol-5-yl 1-Me 04-F-phenyl +++ +++ 11BN pyridin-2-yl 4-CF₃ 1H-pyrazol-4-yl 1,5-dimethyl0 4-F-phenyl +++ +++ 11BO pyridin-2-yl 4-CF₃ 1H-pyrazol-4-yl 04-F-phenyl +++ +++ 11BP pyridin-2-yl 1H-pyrazol-4-yl 1-Me, 3-CF₃ 04-F-phenyl +++ + 11BQ pyridin-2-yl 4-CF₃ phenyl 3,4,5-trifluoro 04-F-phenyl + +++ 11BR pyridin-2-yl 4-CF₃ 1H-pyrazol-3-yl 1-Me 04-Cl-phenyl ++ +++ 11BS pyridin-2-yl 1H-pyrazol-4-yl 0 4-F-phenyl ++ ++11BT pyridin-2-yl 1H-pyrazol-3-yl 1-Me 0 4-CF₃-phenyl + + 11BUthiazol-4-yl phenyl 3,4-difluoro 0 4-F-phenyl + ++ 11BV pyridin-2-yl4-CF3 1H-imidazol-4-yl 1,2-dimethyl 0 4-F-phenyl +++ +++ 11BWpyridin-2-yl 4-CF3 1H-imidazol-5-yl 1,2-dimethyl 0 4-F-phenyl + ++ 11BXpyridin-2-yl 4-CF3 1H-imidazol-2-yl 1-methyl 0 4-F-phenyl ++ +++ 11BYpyridin-2-yl 4-CF3 1H-imidazol-4-yl 1-ethyl 0 4-F-phenyl +++ +++ 11BZthiazol-4-yl 1H-pyrazol-4-yl 1-ethyl 0 4-F-phenyl +++ ++ 11CApyridin-2-yl 1H-pyrazol-4-yl 1-propyl 0 4-F-phenyl +++ +++ 11CBpyridin-2-yl 1H-pyrazol-4-yl 1-(2- 0 4-F-phenyl +++ +++ methoxyethyl)11CC pyrazol-4-yl 1-Me phenyl 3,4-dichloro 0 4-F-phenyl + ++ 11CDpyridin-2-yl 1H-pyrazol-4-yl 1-isopropyl 0 4-F-phenyl +++ +++ 11CE,pyridin-2-yl 4-CF3 1,2,3-triazolyl methyl 0 4-F-phenyl +++ +++ 11CF, +++ 11CG +++ +++ 11CH, pyridin-2-yl 1,2,3-triazolyl ethyl 0 4-F-phenyl+++ +++ 11CI, + ++ 11CJ +++ ++ 11CK, pyridin-2-yl 4-CF3 1,2,3-triazolylethyl 0 4-F-phenyl +++ +++ 11CL, + ++ 11CM +++ +++ 11CN, pyridin-2-yl1,2,3-triazolyl propyl 0 4-F-phenyl +++ +++ 11CO, + ++ 11CP +++ +++11CQ, thiazol-4-yl 1,2,3-triazolyl propyl 0 4-F-phenyl +++ +++ 11CR, ++++ 11CS +++ +++ 11CT, pyridin-2-yl 1,2,3-triazolyl isopropyl 04-F-phenyl +++ +++ 11CU, ++ ++ 11CV +++ ++ 11CW thiazol-4-yl1H-pyrazol-5-yl 1-ethyl 0 4-F-phenyl +++ ++ 11CX pyridin-2-yl 4-CF31H-pyrazol-4-yl 1-propyl 0 4-F-phenyl +++ +++ 11CY thiazol-4-yl1H-pyrazol-4-yl 1-methyl 0 4-F-phenyl ++ ++ 11CZ thiazol-4-yl1H-pyrazol-4-yl 1-propyl 0 4-F-phenyl +++ +++ 11DA thiazol-4-yl1,2,3-triazolyl methyl 0 4-F-phenyl +++ +++ 11DB pyridin-2-yl1,2,3-triazolyl methyl 0 4-F-phenyl +++ +++ 11DC pyridin-2-yl 4-CF31,2,3-triazolyl propyl 0 4-F-phenyl ++ +++ 12 thiazol-2-yl phenyl 3-CF₃0 4-F-phenyl +++ +++ 12A thiazol-2-yl phenyl 3-Me 0 4-F-phenyl +++ +++12B thiazol-2-yl phenyl 3-OMe 0 4-F-phenyl ++ ++ 12C thiazol-2-yl phenyl4-Me, 3-F 0 4-F-phenyl +++ ++ 12D thiazol-2-yl phenyl 0 4-F-phenyl ++++++ 12E thiazol-2-yl phenyl 3-Cl 0 4-F-phenyl +++ ++ 12F pyridin-2-yl5-Me phenyl 3-Me 0 4-F-phenyl +++ +++ 12G pyridin-2-yl 4-Me phenyl 3-Me0 4-F-phenyl +++ +++ 12H pyridin-2-yl 6-Me phenyl 3-Me 0 4-F-phenyl ++++++ 12I thiazol-2-yl phenyl 3-CF₃, 4-F 0 4-F-phenyl +++ ++ 12Jthiazol-2-yl phenyl 3,4,5-trifluoro 0 4-F-phenyl +++ ++ 12K thiazol-2-ylphenyl 3-F, 4-CF₃ 0 4-F-phenyl +++ ++ 12L thiazol-2-yl 5-Me phenyl 3-CF₃0 4-F-phenyl +++ +++ 12M thiazol-2-yl 4-Me phenyl 3-CF₃ 0 4-F-phenyl ++++ 12N thiazol-2-yl phenyl 3,4-dichloro 0 4-F-phenyl ++ +++ 12Othiazol-2-yl 5-Me phenyl 3,4-dichloro 0 4-F-phenyl +++ +++ 12Pthiazol-2-yl phenyl 3,4-difluoro 0 4-F-phenyl +++ ++ 12Q thiazol-2-yl5-Me phenyl 3,4-difluoro 0 4-F-phenyl + +++ 12R thiazol-2-yl 5-Me phenyl3-F, 4-Cl 0 4-F-phenyl ++ +++ 12S thiazol-2-yl 5-Me 1H-pyrazol-3-yl 1-Me0 4-F-phenyl +++ +++ 12T thiazol-2-yl 5-Me 1H-pyrazol-4-yl 1-Me 04-F-phenyl +++ +++ 12U thiazol-2-yl 5-Me 1H-pyrazol-5-yl 1,3-dimethyl 04-F-phenyl + ++ 12V thiazol-2-yl 5-Me 1H-pyrazol-5-yl 1-Me 0 4-F-phenyl++ ++ 12W thiazol-2-yl 1H-pyrazol-5-yl 1-ethyl 0 4-F-phenyl + + 12Xthiazol-2-yl 1H-pyrazol-4-yl 1-ethyl 0 4-F-phenyl +++ ++ 12Ythiazol-2-yl 1H-pyrazol-4-yl 1-propyl 0 4-F-phenyl +++ +++ 12Zthiazol-2-yl 1,2,3-triazolyl methyl 0 4-F-phenyl +++ + 12AA thiazol-2-yl1,2,3-triazolyl propyl 0 4-F-phenyl +++ ++ 13 1H-imidazol- 1-Me phenyl4-Me 0 4-F-phenyl ++ ++ 2-yl 13A 1H-imidazol- 1-Me phenyl 3-Me 04-F-phenyl +++ ++ 2-yl 14 pyridin-2-yl phenyl 3-CONMe2 0 4-F-phenyl +++++ 15 pyridin-2-yl 4-CF₃ 1H-pyrazol-4-yl 1-Et 0 4-F-phenyl +++ +++ 15Apyridin-2-yl phenyl 3-CF₃ 0 pyridin-3-yl +++ ++ 15B pyridin-2-yl phenyl3,4-dichloro 0 phenyl +++ +++ 15C pyridin-2-yl phenyl 3,4-dichloro 03,4- +++ ++ difluorophenyl 15D pyridin-2-yl phenyl 3,5-difluoro, 04-F-phenyl ++ +++ 4-methoxy 16 pyridin-2-yl pyridin-3-yl 6-NMe₂ 04-F-phenyl +++ ++ 17 pyridin-2-yl pyridin-2(1H)- 1-Me 0 4-F-phenyl +one-5-yl 18 pyridin-2-yl 4-CF₃ 1H-pyrazol-4-yl 1-Me 0 4-F-phenyl +++ +++19 thiazol-4-yl phenyl 3,4-dichloro 0 4-F-phenyl +++ +++

In Table 1, GR Binding compounds with a K_(i) value of less than 0.5 nMare designated with +++; compounds with a K_(i) value from 0.5 nM toless than 1.0 nM are designated with ++; and compounds with a K_(i)value of at least 1.0 nM are designated with +. TAT activity with aK_(i) value of less than 20 nM are designated with +++, compounds with aK_(i) value from 20 nM to less than 100 nM are designated with ++; andcompounds with a K_(i) value of at least 100 nM are designated with +.

Example 22. Cell Transrepression Assays

The following protocol describes assays for measuring the effect ofeither GR agonists or antagonists on IL-1β stimulated IL-6 production byA549 cells.

In the GR antagonist mode of the assay compounds are tested for theirability to reverse the suppression of IL-1β stimulated IL-6 productionby dexamethasone. Conversely, in the GR agonist mode of the assaycompounds are tested for their ability to directly inhibit IL-1βstimulated IL-6 production. These assays were adapted from a protocoloutlined by Ali et al., J. Med. Chem. (2004), 47, 2441-2452.

A549 cells were routinely cultured in DMEM media supplemented with 10%(v/v) foetal bovine serum and 2 mM L-glutamine at 37° C., 5%/95% (v/v)CO₂/air (Standard Incubation Conditions). For assay use, cells werecounted and the suspension diluted in DMEM supplemented with 2 mML-glutamine (Assay Media) to 0.66×10⁶ cells/ml. This cell preparationwas then used to seed sterile, tissue culture treated, 384 well plates(20,000 cells/well), which were subsequently kept under StandardIncubation Conditions for 1 hour.

Compounds were solubilised in DMSO to generate a 10 mM stock solution. Arange of 8 test concentrations were generated by diluting the stocksolution in DMSO to 240 μM, followed by 7 serial half log dilutions inDMSO. These test compound solutions were diluted 40-fold into AssayMedia prior to addition to the cells to give a range of final assaycompound concentrations of 10 to 0.003 μM in 0.25% (v/v) DMSO.

Note that the standard GR agonist dexamethasone was tested atconcentrations ranging from 100 to 0.03 nM. Compounds were screened forGR antagonism of an EC₅₀ (10 nM) dexamethasone stimulation.

Compounds were pre-incubated with cells for 1 hour using StandardConditions as previously described, prior to the addition of 10 nMdexamethasone (antagonist mode) or Assay Media (agonist mode) and thenincubated for a further hour.

Cells were then stimulated with IL-113 (final assay concentration 3ng/μL) and incubated for 18 hours to allow sufficient IL-6 to beproduced.

IL-6 in the cell media was measured using an AlphaLISA detection assay(Perkin Elmer). Raw data were converted to IL-6 concentrations byinterpolation of test data against an IL-6 standard curve using GraphPadPrism software.

For the agonist mode assay, IL-6 values were normalised to the maximaleffect of the full agonist dexamethasone and compound concentrationeffect curves were fitted to a 4 parameter logistic equation todetermine EC₅₀ and maximal effect values.

For the antagonist mode assay, IL-6 values were normalised to the effectof 10 nM dexamethasone inhibition of IL-6 production, such that 100%inhibition represented complete reversal of the dexamethasonesuppression of IL-6. Compound IC₅₀ values were determined by plottingcompound concentrations against % inhibition and fitting the data to a 4parameter logistic equation. Compound Ki (inhibitor dissociationconstant) values were estimated by correcting the IC₅₀ values using theCheng-Prusoff equation, assuming that all compounds were competitive GRantagonists with respect to dexamethasone.

Although the foregoing invention has been described in some detail byway of illustration and Example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

What is claimed is:
 1. The compound(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone,having the formula:


2. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound having the formula:


3. A method of modulating a glucocorticoid receptor, comprisingcontacting a glucocorticoid receptor with a compound having the formula:

thereby modulating the glucocorticoid receptor.
 4. The compound(R)-(1-(4-fluorophenyl)-6-4-(trifluoromethyl)phenyl)sulfonyl)-4, 4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, wherein said compound has the formula:


6. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound, or a pharmaceutically acceptable salt of saidcompound, wherein said compound has the formula:


7. A method of modulating a glucocorticoid receptor, comprisingcontacting a glucocorticoid receptor with a compound, or apharmaceutically acceptable salt of said compound, wherein said compoundhas the formula:

thereby modulating the glucocorticoid receptor.
 8. The compound(R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,having the formula:


9. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound having the formula:


10. A method of modulating a glucocorticoid receptor, comprisingcontacting a glucocorticoid receptor with a compound having the formula:

thereby modulating the glucocorticoid receptor.